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Angiotensin-Converting Enzyme 2 Suppresses Pathological Hypertrophy, Myocardial Fibrosis, and Cardiac Dysfunction
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Background— Angiotensin-converting enzyme 2 (ACE2) is a pleiotropic monocarboxypeptidase capable of metabolizing several peptide substrates. We hypothesized that ACE2 is a negative regulator of angiotensin II (Ang II)–mediated signaling and its adverse effects on the cardiovascular system.
Methods and Results— Ang II infusion (1.5 mg · kg−1 · d−1) for 14 days resulted in worsening cardiac fibrosis and pathological hypertrophy in ACE2 knockout (Ace2−/y) mice compared with wild-type (WT) mice. Daily treatment of Ang II–infused wild-type mice with recombinant human ACE2 (rhACE2; 2 mg · kg−1 · d−1 IP) blunted the hypertrophic response and expression of hypertrophy markers and reduced Ang II–induced superoxide production. Ang II–mediated myocardial fibrosis and expression of procollagen type Iα1, procollagen type IIIα1, transforming growth factor-β1, and fibronectin were also suppressed by rhACE2. Ang II–induced diastolic dysfunction was inhibited by rhACE2 in association with reduced plasma and myocardial Ang II and increased plasma Ang 1-7 levels. rhACE2 treatment inhibited Ang II–mediated activation of protein kinase C-α and protein kinase C-β1 protein levels and phosphorylation of the extracellular signal-regulated 1/2, Janus kinase 2, and signal transducer and activator of transcription 3 signaling pathways in wild-type mice. A subpressor dose of Ang II (0.15 mg · kg−1 · d−1) resulted in a milder phenotype that was strikingly attenuated by rhACE2 (2 mg · kg−1 · d−1 IP). In adult ventricular cardiomyocytes and cardiofibroblasts, Ang II–mediated superoxide generation, collagen production, and extracellular signal-regulated 1/2 signaling were inhibited by rhACE2 in an Ang 1-7–dependent manner. Importantly, rhACE2 partially prevented the development of dilated cardiomyopathy in pressure-overloaded wild-type mice.
Conclusions— Elevated Ang II induced hypertension, myocardial hypertrophy, fibrosis, and diastolic dysfunction, which were exacerbated by ACE2 deficiency, whereas rhACE2 attenuated Ang II– and pressure-overload–induced adverse myocardial remodeling. Hence, ACE2 is an important negative regulator of Ang II–induced heart disease and suppresses adverse myocardial remodeling.
Received November 4, 2009; accepted June 14, 2010.
Activation of the renin-angiotensin system (RAS) and the subsequent generation of angiotensin (Ang) II are important mediators of myocardial fibrosis, pathological hypertrophy, and heart failure.1–3 Pathological hypertrophy and increased myocardial interstitial fibrosis contribute to increased ventricular wall stiffness, thereby impairing cardiac diastolic function, and represent an important risk factor for heart failure in experimental models and patients.4–6 Drugs that target Ang II and the Ang II type 1 receptor (AT1) are widely used for the treatment of cardiovascular diseases such as hypertension, myocardial infarction, and heart failure.7 Angiotensin-converting enzyme 2 (ACE2) is a pleiotropic monocarboxypeptidase capable of metabolizing a range of peptide substrates, including Ang I, Ang II, des-Arg9-bradykinin, apelin-13, and opioids.8–11 Ang 1-7, one of the major enzymatic products of ACE2, has been shown to reduce Ang II–induced cardiac hypertrophy and remodeling and pressure-overload–induced heart failure.12,13 ACE2-deficient mice can develop impaired cardiac function with adverse ventricular remodeling, enhanced oxidative stress, and inflammatory cytokine expression.14,15
Clinical Perspective on p 728
In the present study, we directly assessed the hypothesis that ACE2 is a negative regulator of Ang II–mediated heart disease. Ang II–mediated oxidative stress, cardiac hypertrophy, and fibrosis are exacerbated in ACE2-deficient mice, which results in worsening of diastolic dysfunction. Recombinant human ACE2 (rhACE2) attenuated Ang II–mediated hypertension, ventricular hypertrophy, and fibrosis and improved diastolic dysfunction, with a marked reversal of Ang II–induced activation of pathological signaling pathways. In response to pressure overload, rhACE2 partially attenuated the adverse myocardial remodeling. These beneficial effects of rhACE2 correlated with the reduction in Ang II and increase in Ang 1-7 levels. We conclude that ACE2 plays a pivotal role in the inhibition of myocardial hypertrophy, fibrosis, and cardiac dysfunction, and rhACE2 represents a novel therapeutic strategy for cardiovascular disorders.
Please see the online-only Data Supplement for additional details.
Experimental Animals and Protocols
Mutant mice were backcrossed into a pure C57BL/6 background for >10 generations as described previously.15,16 Ten-week-old male ACE2 knockout (ACE2KO) mice (Ace2−/y) and their littermate wild-type (WT; Ace2+/y) mice were used. An osmotic minipump (model 1002, Alza Corp, Palo Alto, Calif) was implanted subcutaneously at the dorsum of the neck to infuse a pressor dose of Ang II (1.5 mg · kg−1 · d−1), a subpressor dose of Ang II (0.15 mg · kg−1 · d−1), or saline (vehicle) for 14 days. Ang II–infused WT mice were then treated with placebo or rhACE2 (2 mg · kg−1 · d−1 IP). All experiments were performed in accordance with institutional guidelines and the standards of the Canadian Council on Animal Care.
Aortic Banding
The aortic banding model was used to generate pressure-overload–induced heart failure in 8- to 9-week-old male C57/BL6 WT mice, as we have described previously.17 After 6 weeks of pressure overload, banded WT mice were randomized to receive rhACE2 (2 mg · kg−1 · d−1 IP) or placebo for 3 weeks.
Tail-Cuff Systolic Blood Pressure
Systolic blood pressure of each mouse was measured by the tail-cuff method with an IITC blood pressure monitoring system (IITC Life Science, Woodland Hills, Calif).
Echocardiography and Tissue Doppler Imaging
Transthoracic echocardiography was performed and analyzed in a blinded manner as described previously with a Vevo 770 high-resolution imaging system equipped with a 30-MHz transducer (RMV-707B; VisualSonics, Toronto, Canada).18
Trichrome and picrosirius red staining and visualization and analysis of collagen volume fraction were performed as described previously.17
TaqMan Real-Time Polymerase Chain Reaction and Western Blot Analysis
RNA expression levels of various genes and Western blot analyses were determined as described previously.15–17 The primers and probes for mRNA expression analysis by TaqMan (Applied Biosystems, Foster City, Calif) real-time polymerase chain reaction are listed in online-only Data Supplement Table I; 18S ribosomal RNA was used as the endogenous control. Antibodies were obtained from Santa Cruz Biotechnology (Santa Cruz, Calif), Cell Signaling Inc (Danvers, Mass), and R&D Systems (Minneapolis, Minn).15–17
Generation and Characterization of rhACE2
The extracellular domain of human ACE2 (amino acid residues 1 to 740, molecular weight 101 kDa)19 was expressed recombinantly in Chinese hamster ovary (CHO) cells as described previously (online-only Data Supplement).20
Angiotensin Peptide Measurement
Plasma Ang II and Ang 1-7 and myocardial Ang II levels were measured by radioimmunoassay in the Hypertension and Vascular Research Center core laboratory at Wake Forest University School of Medicine as described previously.14,16
Invasive Pressure-Volume Measurements
Invasive pressure-volume measurements were made in nonintubated and anesthetized mice (1% isoflurane mixed with 100% O2) with the SPR-869 microtip catheter and the Millar pressure-volume system MPVS-400 (Millar Instruments, Houston, Tex) as described previously21 at 3 to 4 hours after removal of the osmotic pumps. In aortic-banded mice, only invasive pressure measurements were obtained.
Isolation and Culture of Adult Cardiomyocytes and Cardiofibroblasts
Adult murine left ventricular (LV) cardiomyocytes and cardiofibroblasts were isolated and cultured as described previously.22
Dihydroethidium Fluorescence and Lucigenin-Enhanced Chemiluminescence
Dihydroethidium, an oxidative fluorescent dye, was used to measure superoxide (O2−) levels in cultured cardiomyocytes and heart tissues from ACE2KO and WT mice as described previously.16 Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in cultured cardiomyocytes and hearts of mice was quantified by lucigenin-enhanced chemiluminescence as described previously.15,16
Statistical Analysis
Results are shown as mean±SEM. Statistical analysis was performed with SPSS 11.5 software either by ANOVA followed by multiple-comparison testing (Student-Neuman-Keuls test) or the Fisher exact test as appropriate. P<0.05 was considered statistically significant.
Ang II–Induced Myocardial Hypertrophy and Fibrosis, Diastolic Dysfunction, and Oxidative Stress Are Exacerbated by the Loss of ACE2
To determine the regulatory role of ACE2 in Ang II–induced heart disease, we subjected ACE2KO (Ace2−/y) and WT (Ace2+/y) mice to a 14-day period of Ang II infusion (1.5 mg · kg−1 · d−1). Echocardiographic M-mode images (Figure 1A) and 2-dimensional short-axis midventricular views (Figure 1B) revealed normal systolic function with no change in fractional shortening, ejection fraction, or velocity of circumferential shortening between WT and ACE2KO mice (online-only Data Supplement Table II). Notably, there was greater concentric remodeling in the ACE2KO mice in response to chronic stimulation by Ang II, with a greater increase in ventricular wall thickness (Figures 1A and 1B; online-only Data Supplement Table II). Concentric remodeling of the LV resulted in diastolic dysfunction as assessed by transmitral Doppler filling and tissue Doppler imaging. In Ang II–treated WT mice, the transmitral A wave was increased (with a reduced E/A ratio) with reduced E′ (and increased E/E′ ratio; Figures 1C and 1D; online-only Data Supplement Table II). LV isovolumetric relaxation time was increased significantly, whereas the E′/A′ showed greater reduction, primarily due to marked elevation of the A′ wave in Ang II–treated ACE2KO mice compared with WT mice (Figures 1C and 1D; online-only Data Supplement Table II).
Interestingly, myocardial ACE2 protein level in WT mice was reduced by 60% in response to Ang II (Figure 1E), which may have facilitated Ang II–induced myocardial injury. Gravimetric analysis showed that Ang II infusion resulted in a greater increase in the heart weight–tibia length ratio and LV weight–tibia length ratio in ACE2KO than in WT mice (Figure 1F). Real-time polymerase chain reaction analysis revealed that loss of ACE2 augmented Ang II–induced mRNA expression of molecular markers of pathological hypertrophy, including brain natriuretic peptide (Figure 1G) and α-skeletal actin (Figure 1H), without having a differential effect on β-myosin heavy chain mRNA expression (Figure 1I) or protein levels (Figure 1J). Ang II–mediated NADPH oxidase activation and superoxide generation are pivotal mechanisms of Ang II–mediated injury in the cardiovascular system.3,23,24 Consistent with the exacerbation of Ang II pathological effects in ACE2KO mice, Ang II–induced superoxide production (Figures 2A and 2B) and NADPH oxidase activation (Figure 2B) were greater in ACE2KO mice than in WT mice, likely driven by the greater elevation in myocardial Ang II levels in ACE2KO mice (Figure 2C). Ang II is a well-known activator of increased tissue fibrosis via its profibrotic effects.1–3 Ang II resulted in greater mRNA expression of procollagen type Iα1 (Figure 2D), procollagen type IIIα1 (Figure 2E), fibronectin (Figure 2F), and transforming growth factor-β 1 (TGF-β1; Figure 2G) in ACE2KO mice than in WT mice. These molecular footprints of increased fibrosis were confirmed by histological analyses (Figures 2H and 2I) that showed greater interstitial and perivascular myocardial fibrosis in ACE2KO mice. The collagen volume fraction showed a greater increase in ACE2KO mice (15.9±2.1%; n=8) than in WT mice (9.1±1.8%; n=8; P<0.05) in response to Ang II. Collectively, these data show that loss of ACE2 increases myocardial Ang II levels and worsens concentric remodeling, which results in greater deterioration of diastolic dysfunction in response to exogenous Ang II.
Treatment With rhACE2 Attenuates Ang II–Mediated Cardiac Hypertrophy and Fibrosis and Pathological Signaling
The purity, molecular weight, and identity of rhACE2 were confirmed by high-performance liquid chromatography, SDS-PAGE, and Western blot analyses (online-only Data Supplement Figure I). Human ACE2 shares 65% homology with rodent ACE2 with a conserved catalytic site (online-only Data Supplement Figure II),14,19 and rhACE2 (1 μg/mL) produced marked and similar elevations in plasma ACE2 activity in murine and human plasma (online-only Data Supplement Figures IIIA and IIIB). Plasma ACE2 activity was markedly increased at 1 and 2 weeks after initiation of rhACE2 at 2 mg · kg−1 · d−1 IP in WT mice (online-only Data Supplement Figure IIIC). WT mice showed a marked increase in LV wall thickness (online-only Data Supplement Table III), as illustrated by M-mode imaging (Figure 3A) and a short-axis view (Figure 3B), without deterioration in systolic function (Figure 3A; online-only Data Supplement Table III), in response to Ang II. The primary functional abnormality in these mice was diastolic dysfunction characterized by increased A-wave amplitude (with resultant reduction in the E/A ratio) and reduced E′ (with resultant reduction in the E′/A′ ratio; Figures 3C and 3D; online-only Data Supplement Table III). The use of rhACE2 inhibited Ang II–induced hypertrophy on the basis of LV wall thickness (Figures 3A and 3B; online-only Data Supplement Table III), with reversal of diastolic dysfunction (Figures 3C and 3D; online-only Data Supplement Table III). Invasive pressure-volume hemodynamic assessment confirmed Ang II–induced diastolic dysfunction characterized by elevated LV end-diastolic pressure, increased slope of the end-diastolic pressure-volume relationship, and an increased LV relaxation time constant, which were all reduced by treatment with rhACE2 (online-only Data Supplement Figure IV).
Morphometric analyses further confirmed the marked antihypertrophic effects of rhACE2 against Ang II–induced hypertrophy (Figure 3E), with reduced expression of hypertrophy markers (Figures 3F through 3H). Normalization of increased β-myosin heavy chain mRNA expression was confirmed by Western blot analysis (Figure 3I). Both matrix metalloproteinase-2 and ADAM12 (a disintegrin and metalloprotease 12), which have been linked to agonist-mediated hypertrophy, were upregulated by Ang II and suppressed by rhACE2 (Figures 3J and 3K), consistent with the effects on myocardial hypertrophy. Hence, rhACE2 reduced the Ang II–induced hypertrophy associated with improvement in diastolic dysfunction to levels comparable to those in the vehicle-treated group. WT mice that received rhACE2 showed reduced Ang II–induced mRNA expression of the fibrosis-associated genes procollagen type Iα1 (Figure 4A), procollagen type IIIα1 (Figure 4B), fibronectin (Figure 4C), and TGF-β1 (Figure 4D). Picrosirius red (Figure 4E) and trichrome (Figure 4F) staining showed that Ang II–triggered interstitial and perivascular fibrosis was suppressed by rhACE2 treatment. Collagen volume fraction was reduced from 11.6±1.8% in WT mice treated with Ang II and placebo (n=8) to 3.2±1.3% in WT mice treated with Ang II and rhACE2 (n=8; P<0.05). Given the critical role of Ang II and ACE2 in kidney disease,20,25,26 we also examined the impact of rhACE2 on Ang II–induced renal fibrosis. Ang II resulted in a marked increase in the expression of procollagen type Iα, procollagen type IIIα, α-smooth muscle actin, and TGF-β1, as well as in collagen I and III protein levels (online-only Data Supplement Figure V), whereas picrosirius red staining showed increased tubulointerstitial fibrosis in response to Ang II (online-only Data Supplement Figure V). Treatment with rhACE2 largely attenuated these markers of increased tubulointerstitial fibrosis (online-only Data Supplement Figure V). Clearly, rhACE2 can suppress the hypertrophic and profibrotic effects of Ang II, thereby reducing Ang II–induced diastolic dysfunction.
Consistent with the induction of hypertrophy and fibrosis, Ang II infusion caused activation and elevated phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK 1/2; Figure 4G), Janus kinase 2 (JAK2; Figure 4H), and signal transducer and activator of transcription 3 (STAT3; Figure 4I) without altering p38 mitogen-activated protein kinase (Figure 4J) in WT mice. Interestingly, rhACE2 inhibited the increased phosphorylation of extracellular signal-regulated (ERK) 1/2 (Figure 4G) while reducing the phosphorylation of JAK2 and STAT3 by 50% to 60% (Figures 4H and 4I). Western blot analyses also revealed increased protein expression of protein kinase C (PKC)-α (Figure 4K) and PKC-β1 (Figure 4L) in response to Ang II, which was suppressed strikingly by the administration of rhACE2. These observations confirm that the potent antihypertrophic and antifibrotic effects mediated by rhACE2 are mediated, at least in part, via suppression of Ang II–induced ERK1/2, JAK2-STAT3, and PKC signaling pathways.
Treatment With rhACE2 Reverses Ang II–Induced Oxidative Stress and Modulates Angiotensin Peptide Levels
The structural, functional, and biochemical rescue provided by rhACE2 could be linked to a reduction in Ang II or increased Ang 1-7 signaling. To test this hypothesis, we measured plasma and myocardial Ang II levels, as well as levels of the product of ACE2 metabolism of Ang II, plasma Ang 1-7. Ang II infusion led to a predictable increase in plasma and myocardial Ang II levels, both of which were both reduced by 60% with rhACE2 treatment (Figures 5A and 5B). In WT mice that received Ang II, plasma Ang 1-7 levels increased and were further elevated by rhACE2, which provides definitive evidence that ACE2 is an important enzyme that degrades Ang II into Ang 1-7 in vivo (Figure 5C). Infusion of Ang II for 14 days resulted in a 64±5-mm Hg increase in peak systolic blood pressure over vehicle-infused WT mice (Figure 5D), whereas rhACE2 treatment partially reduced the pressor effect of Ang II without affecting basal systolic blood pressure in vehicle-treated mice (Figure 5D). Exposure to elevated Ang II resulted in a predictable and significant increase in superoxide levels in the heart in vivo (Figures 5E through 5J). Recombinant human ACE2 largely prevented this increase in superoxide production (Figure 5K) via suppression of Ang II–induced activation of the NADPH oxidase system (Figure 5L). The superoxide scavenger polyethylene glycol–superoxide dismutase (500 U/mL; Figure 5K) and the NADPH oxidase inhibitor diphenyleneiodonium (10 μmol/L; Figure 5L), were used to confirm these measurements. These results showed that rhACE2 can reverse pathological signaling and superoxide production in association with reduced Ang II or increased Ang 1-7 levels.
Treatment With rhACE2 Prevents Subpressor Ang II–Mediated and Pressure-Overload–Induced Pathological Remodeling
A low dose of Ang II (0.15 mg · kg−1 · d−1 for 2 weeks) did not change systolic blood pressure (online-only Data Supplement Figure VI). Echocardiographic 2-dimensional short-axis midventricular views (Figure 6A) and M-mode images (Figure 6B) revealed normal systolic function with no change in fractional shortening, ejection fraction, or velocity of circumferential shortening but with a mild but measurable increase in LV wall thickness in response to the subpressor dose of Ang II (Figures 6A, 6B, and 6E; online-only Data Supplement Table IV). The mild concentric remodeling of the LV resulted in diastolic dysfunction as assessed by transmitral Doppler filling (Figure 6C) and tissue Doppler imaging (Figure 6D), with a reduced E/A ratio (Figure 6F) and increased E′/A′ ratio (Figure 6H; online-only Data Supplement Table IV). Morphometric assessment (Figure 6I) and analysis of the expression of the hypertrophy genes α-SA (α-skeletal actin; Figure 6J), BNP (brain natriuretic peptide; Figure 6K), and β-MHC (β-myosin heavy chain; Figure 6L) showed a measurable increase in response to Ang II, whereas the Ang II–induced mRNA expression of the fibrosis-associated genes procollagen type Iα1 (Figure 6M), procollagen type IIIα1 (Figure 6N), fibronectin (Figure 6O), and TGF-β1 (Figure 6P) resulted in a mild degree of myocardial fibrosis (Figure 6Q). Treatment with rhACE2 attenuated the low-dose Ang II–induced myocardial hypertrophy, diastolic dysfunction, and myocardial fibrosis (Figures 6A through 6Q). These results show that rhACE2 can directly suppress Ang II–mediated pathological hypertrophy and diastolic dysfunction independent of systemic hemodynamic effects.
In the clinically relevant pressure-overload model of heart failure, there was an early and marked downregulation of myocardial ACE2 protein (Figure 7A), which implies that loss of ACE2 can facilitate adverse myocardial remodeling. We next evaluated the effects of rhACE2 on the pathological hypertrophy and functional response to pressure overload. After 6 weeks of pressure overload, WT mice were randomized to receive placebo or rhACE2 (2 mg · kg−1 · d−1 IP) for 3 weeks. Treatment with rhACE2 for 3 weeks partially reduced the hypertrophy (Figure 7B) and resulted in a partial improvement in fractional shortening (Figure 7C) and prevention of ventricular dilation (Figure 7D). Invasive hemodynamic assessment confirmed partial rescue of functional deterioration, with a reduction in the elevated LV end-diastolic pressure (Figure 7E) and partial restoration of myocardial performance as measured by +dP/dt (Figure 7F) and −dP/dt (Figure 7G). Molecular markers of pathological hypertrophy, α-skeletal actin (Figure 7H), brain natriuretic peptide (Figure 7I), and β-myosin heavy chain (Figure 7J), and expression of procollagen type Iα1 (Figure 7K) and procollagen type IIIα1 (Figure 7L) all showed a near normalization that resulted in a reduction in myocardial fibrosis (Figure 7M) in response to rhACE2. These results clearly demonstrate that rhACE2 can provide therapeutic benefits against pathological myocardial remodeling in a clinically relevant model of heart failure.
ACE2 Is a Negative Regulator of Oxidative Stress and Collagen Production in Cultured Adult Cardiomyocytes and Cardiofibroblasts
The in vivo action of Ang II can result in a wide array of effects, including changes in blood pressure and hemodynamic load. To evaluate a more direct effect of rhACE2 on Ang II signaling, we examined the impact of rhACE2 on Ang II effects in these cultured cells. We first confirmed the presence of ACE2 in cultured adult murine cardiomyocytes and cardiofibroblasts (Figure 8A). Dihydroethidium fluorescence imaging showed a marked increase in superoxide production in response to Ang II (100 nmol/L) in cardiomyocytes that was blocked by rhACE2 in a dose-dependent manner and by biological superoxide degradation with polyethylene glycol–superoxide dismutase (Figures 8A through 8D). NADPH oxidase activity showed a similar increase with Ang II that was blocked by increasing doses of rhACE2 and by the chemical inhibitor of NADPH oxidase, diphenyleneiodonium (Figure 8C). Preincubation with the Mas receptor peptide antagonist D-Ala7-Ang 1-727 largely prevented the suppression of Ang II–mediated superoxide generation (Figures 8B and 8E) and NADPH oxidase activation (Figure 8F), which confirmed that enhanced Ang 1-7 signaling is a key mediator of rhACE2 action. Expression analyses showed that Ang II–induced expression of procollagen type Iα (Figure 8G), procollagen type IIIα (Figure 8H), fibronectin (Figure 8I), TGF-β1 (Figure 8J), and α-smooth muscle actin (Figure 8K) was reduced strikingly by rhACE2. The increased phosphorylation of ERK1/2 in cardiomyocytes and cardiofibroblasts in response to Ang II was prevented in part by rhACE2, which was reversed by cotreatment with D-Ala7-Ang 1-7 (Figure 8L). These in vitro results proved that rhACE2 can mediate direct effects on adult cardiomyocytes and cardiofibroblasts, which are mediated in part by the promotion of Ang 1-7 signaling.
ACE2 is the first known homolog of human ACE and functions as a pleiotropic monocarboxypeptidase responsible for the degradation of a range of peptides with a high catalytic efficiency.8–10 In the present study, we clearly define the critical role of ACE2 in mediating conversion of Ang II to Ang 1-7 and as a negative regulator of Ang II–induced heart disease. The downregulation of ACE2 by Ang II and aortic banding is likely a key player in the adverse remodeling that is characteristic of agonist-mediated and pressure-overload–induced heart disease. Ang II, a major bioactive effector of the RAS, is aberrantly activated in heart disease, eliciting a variety of biological actions spanning the diverse roles of the RAS in cardiovascular homeostasis and disease.1–3,7 ACE2 has emerged as an important determinant of heart disease,16,28 and increasing serum ACE2 activity correlates with worsening LV function and poor clinical outcomes in patients with heart failure.29
The present data show that in a setting of elevated Ang II levels, absence of ACE2 results in greater pathological ventricular hypertrophy and fibrosis, which results in worsening diastolic dysfunction. In contrast, treatment with rhACE2 prevented Ang II–induced hypertrophy and myocardial fibrosis. Mechanistically, we linked these changes to a greater elevation in myocardial Ang II levels, which led to enhanced NADPH oxidase activation and superoxide generation, which were important mediators of pathological hypertrophy and fibrosis in the ACE2KO hearts, and to a corresponding reduction in response to rhACE2.30 The development of myocardial fibrosis and pathological hypertrophy results in diastolic dysfunction and diastolic heart failure due to increased myocardial stiffness.5 Importantly, Ang II–induced diastolic dysfunction was completely ameliorated by rhACE2, in association with marked reduction of hypertrophy and myocardial fibrosis. In addition, using a subpressor dose of Ang II and the pressure-overload model of heart failure, we showed that rhACE2 can have direct cardioprotective actions independent of systemic hemodynamic effects. The present findings are consistent with the ability of increased ACE2 to blunt the high blood pressure and myocardial damage seen in rat models.31,32 The protective effects of rhACE2 against pressure-overload–induced heart failure are consistent with the exacerbation of pressure-overload heart failure in ACE2KO mice28 and support a key role of the RAS in the cardiac response to pressure overload.33
Ang II activates a plethora of signaling cascades, including those of the mitogen-activated protein kinase, PKC, and JAK2-STAT3 signaling pathways, which results in myocardial hypertrophy and increased fibrosis.1,3,34,35 Ang II activation of PKC signaling and enhancement of nuclear accumulation of STAT family members are associated with cardiac fibrosis and hypertrophy,36,37 whereas inhibition of these pathways attenuates collagen deposition and myocardial fibrosis, hypertrophy, and diastolic dysfunction.38,39 Ang II–AT1-mediated activation of ERK1/2 plays a key role in the downregulation of ACE2 expression, which leads to an amplification of Ang II–mediated effects.40 The abolishment of ERK1/2, JAK2-STAT3, and PKC signaling by rhACE2 is responsible, at least in part, for attenuation of Ang II–induced myocardial hypertrophy and fibrosis and improvement of diastolic dysfunction.
rhACE2 reduced the plasma and myocardial Ang II levels and increased plasma Ang 1-7 levels. This critical switch in the biochemical milieu had a pivotal role in minimizing Ang II–induced cardiac and vascular pathology. Ang 1-7 can suppress Ang II–mediated myocardial hypertrophy and fibrosis independent of blood pressure.12,13 Importantly, rhACE2 did not alter baseline plasma Ang II, Ang 1-7, or blood pressure in WT mice, which suggests that substrate availability is a limiting factor in ACE2 enzymatic activity.41 We propose that ACE2 functions as a negative regulator of the RAS predominantly in the setting of increased Ang II, as in heart disease. ACE2 is expressed and functional in cardiomyocytes and cardiofibrobasts and acts as a local negative regulator of the RAS independent of a blood pressure–lowering effect. Cardiac fibroblasts express AT1 receptors and Ang 1-7 receptors,42 and Ang II is known to induce production of collagen and TGF-β1,1,42 both of which were largely inhibited by rhACE2.
In summary, in the setting of elevated Ang II, loss of ACE2 increases Ang II–induced myocardial hypertrophy and fibrosis and increases oxidative stress, which results in worsening diastolic dysfunction. In contrast, rhACE2 prevents Ang II–induced hypertrophy and fibrosis in part because of enhanced Ang 1-7 signaling. In the pressure-overload model of heart failure, rhACE2 partially prevented the functional deterioration of cardiac function and the degree of pathological remodeling. ACE2 can act as a protective mechanism in the heart to limit the pathological effects of an activated systemic and/or local RAS.
Dr Oudit is a Clinician-Investigator Scholar of the Alberta Heritage Foundation for Medical Research and a Distinguished Clinician Scientist of the Heart and Stroke Foundation of Canada and Canadian Institutes of Health Research, and Dr Kassiri is a New Investigator of the Heart and Stroke Foundation of Canada. Dr Zhong was also supported by the National Natural Science Foundation of China. We acknowledge technical assistance from the Cardiovascular Research Centre core facilities at the University of Alberta and support from an Alberta HEART Interdisciplinary Team Grant.
Sources of Funding
We acknowledge financial support from the Canadian Institute for Health Research (Dr Oudit, grant No. 86602; Dr Kassiri, grant No. 84279), the Alberta Heritage Foundation for Medical Research (Drs Oudit and Zhong), and EuGeneHeart (EU 6th Framework Programs), the Austrian National Bank, and the Institute of Molecular Biotechnology, Austria (Dr Penninger).
Dr Shuster is Chief Operating Officer of Apeiron Biologics and owns stock in the company; Dr Loibner is Chief Executive Officer of Apeiron Biologics and owns stock in the company; and Dr Penninger is the founder of Apeiron Biologics and owns stock in the company. The remaining authors report no conflicts.
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Tsai CT, Lai LP, Kuo KT, Hwang JJ, Hsieh CS, Hsu KL, Tseng CD, Tseng YZ, Chiang FT, Lin JL. Angiotensin II activates signal transducer and activators of transcription 3 via Rac1 in atrial myocytes and fibroblasts: implication for the therapeutic effect of statin in atrial structural remodeling. Circulation. 2008; 117: 344–355.
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Activation of the tissue and systemic renin-angiotensin system and the generation of angiotensin II play a key role in cardiovascular diseases. Angiotensin-converting enzyme 2 (ACE2) is the first known homolog of human ACE and functions as a pleiotropic monocarboxypeptidase. In the present study, we showed that ACE2 negatively regulates the pathophysiological effects of a pressor and subpressor dose of angiotensin II on myocardial structure and function. Whereas loss of ACE2 increases angiotensin II levels, increased ACE2 action by the use of recombinant human ACE2 lowered angiotensin II and increased angiotensin 1-7 levels in vivo, which provides definitive evidence for a key role of ACE2 in the metabolism of angiotensin II. These changes in peptide levels were associated with a plethora of molecular and cellular alterations, including inhibition of superoxide production and reduced activation of various key signaling pathways. The resultant phenotypic changes, characterized by increased myocardial and renal fibrosis, pathological hypertrophy, and diastolic dysfunction, were inhibited by ACE2. The beneficial effects of recombinant human ACE2 were also demonstrated in the clinically relevant model of pressure-overload–induced heart failure. In response to exogenous angiotensin II and pressure overload, ACE2 levels were decreased, thereby perpetuating the pathological effects of angiotensin II. The direct effects of angiotensin II on adult ventricular cardiomyocytes and cardiac fibroblasts were suppressed by recombinant human ACE2 in an angiotensin 1-7–dependent manner. Recombinant human ACE2 can provide a novel therapeutic approach for patients with cardiovascular disease.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.110.955369/DC1.
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- Angiotensin-Converting Enzyme 2 Suppresses Pathological Hypertrophy, Myocardial Fibrosis, and Cardiac DysfunctionJiuChang Zhong, Ratnadeep Basu, Danny Guo, Fung L. Chow, Simon Byrns, Manfred Schuster, Hans Loibner, Xiu-hua Wang, Josef M. Penninger, Zamaneh Kassiri and Gavin Y. OuditCirculation. 2010;122:717-728, originally published August 16, 2010http://dx.doi.org/10.1161/CIRCULATIONAHA.110.955369
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- Angiotensin-Converting Enzyme 2 Suppresses Pathological Hypertrophy, Myocardial Fibrosis, and Cardiac DysfunctionJiuChang Zhong, Ratnadeep Basu, Danny Guo, Fung L. Chow, Simon Byrns, Manfred Schuster, Hans Loibner, Xiu-hua Wang, Josef M. Penninger, Zamaneh Kassiri and Gavin Y. OuditCirculation. 2010;122:717-728, originally published August 16, 2010http://dx.doi.org/10.1161/CIRCULATIONAHA.110.955369
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text:
In Amy Sohn's new novel, The Actress, a millennial starlet is explicitly cast as the girlfriend of an older, closeted gay male heartthrob. Maddy Freed, an indie actress whose star is on the rise, is invited to read for an Oscar-worthy movie role opposite Steven Weller, two decades her senior. Maddy is instantly taken with Steven, a celebrated actor with a multi-decade career.
Steven has always been ripe for tabloid fodder given the endurance of his career. But despite cycling through an array of girlfriends (and one wife) over the years, gay rumors tail him constantly. Maddy, aware of the rumors, dismisses them as such and pursues a romantic relationship anyway. But as the two actors pursue different projects and end up shooting in different locations, Steven's gay rumors resurface again and again in the tabloids, with even Maddy second-guessing the legitimacy of their relationship.
I emailed with Amy about queer representation in the media and celebrity narratives.
Via Pete

subset: commoncrawl


text:
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text:
I was so glad that my life was more like the breakfast club and less like American Pie.
Unintended consequences indeed, I know of at least one woman emblazened on my unconscious who has led to my seeking out, unconsciously, similar women. The legacies, the legacies. Why can no one foresee them?


text:
Last update: Monday 24 October 2016 [136 news items]
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Explore Shea'S Animals, Animals Picks and more!
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Shea Moisture Styling Gel NWT never used or opened.. Shea Moisture mongongo & hemp seed oils high porosity moisture seal styling gel. No sulfates, parabens, phthalates, animal testing ETC! Color safe. Specifically for low moisture-retention (dry), curly and coily hair :) Shea Moisture Makeup
Ella Pomegranate shea butter hand cream body/hand lotion with shea butter 25ml. brand new unopened. cruelty free, not tested on animals. Please comment with any questions and feel free to check out my other listings. Thank you (: ella Other
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I hope that lion does not want a hot dog :))
I thank a dog everyday of my life. I also thank God for the fortune of loving and knowing what dogs are all about, which have helped me realized, they are all about love and loyalty and most of the time they know about those two things, better than some humans.
babyanimalposts: "feeling sad? you need this blog on your dash! "
the-blonde-belle: " Look at my goofball of a dog. She's more photogenic than me 🍂🐶🍁 "


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Used Dodge Grand Caravan for Sale in Bakersfield, CA
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|by wniver
"Great vehicle for the money but need electrical issues fixed."
Lots of electrical issues with the vehicle, like power surges (pulsating lighting), Bad wire harnesses for power doors, bad power door motors, bad power window motors, bad breaking wiring all together. It gets great gas mileage though and has great handling and feels very safe and comfortable. The sunroof is a great option to have also, let me tell...
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Best Underwater Photography 1. Grand Cayman, Cayman Islands 2. Belize Atolls 3. Exumas, Bahamas 4. Riviera Maya, Mexico (pictured) 5. St. Croix, U.S. Virgin Islands eastern side of the Yucatan Peninsula, ramble down coastal Highway 307 through Quintana Roo to some of the best dive sites in Mexico. Playa del Carmen world-class drift diving at Palancar Reef & Columbia Wall , plus bull-shark dives. It is also reach remote Chinchorro Banks. Freshwater caverns scubadiving.com/rivieramaya
Scuba Safety is so important even to refresh your memory after diving for years and years, this should and probably is embedded in the way you dive!
need to build this
Where to dive in Europe? Here are the best dive spots in the continent.
deep dives into a turquoise oasis
Check out this underwater museum of art in Cancun, Mexico Then share your art expertise at www.myreplyis.com
Dolphin Dive - Anthony's Key Resort - Roatan - Honduras I have done this here! Woo Hoo!
A diver works in Bonaire's coral nursery. Coral Restoration Foundation Bonaire. @coralcrf
From birth, man carries the weight of gravity on his shoulders. He is bolted to earth. But man has only to sink beneath the surface and he is free.– Jacques Yves Cousteau #scuba #diving #quotes #inspirationalquotes
#Underwater #adventures are one of my favorite things.


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Heparin lowers the blood pressure in hypertensive rats.
This study describes the effect of heparin on blood pressure, cardiac output, and total peripheral resistance in spontaneously hypertensive and one-kidney, one clip Goldblatt hypertensive rats. Administration of heparin (200 units/day/rat) for 8 weeks to young (6-week-old) spontaneously hypertensive rats (SHR) resulted in an attenuated rise in blood pressure; mean blood pressure in heparin-treated SHR (180 +/- mm Hg) was significantly lower (p less than 0.05) than that in control SHR (205 +/- 7 mm Hg). Similar heparin treatment started immediately after the induction of one-kidney, one clip (Goldblatt) hypertension reduced the rise in blood pressure. After 4 weeks of treatment, heparin-treated Goldblatt hypertensive rats had much lower blood pressure (150 +/- 4 mm Hg) than did control rats (7178 +/- 8 mm Hg). The difference was highly significant (p less than 0.01). Similarly, heparin treatment also lowered the blood pressure in rats with developed Goldblatt hypertension. After the cessation of heparin treatment, the blood pressure returned to pretreatment level in these rats. When compared to vehicle-treated rats, heparin-treated animals with either spontaneous or Goldblatt hypertension concomitantly exhibited a significant increase in cardiac output, and significant decreases in total peripheral resistance and packed cell volume. Further, the left ventricular weight to body weight ratio was significantly lower (p less than 0.05) in heparin-treated than control animals. Since a relationship seems to exist between an increase in packed cell volume and blood viscosity and the rise in arterial pressure, this blood-pressure-lowering effect of heparin may be attributed to a decrease in packed cell volume.
- Copyright © 1982 by American Heart Association
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- Heparin lowers the blood pressure in hypertensive rats.D Susic, A K Mandal and D KenteraHypertension. 1982;4:681-685, originally published September 1, 1982http://dx.doi.org/10.1161/01.HYP.4.5.681
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- Heparin lowers the blood pressure in hypertensive rats.D Susic, A K Mandal and D KenteraHypertension. 1982;4:681-685, originally published September 1, 1982http://dx.doi.org/10.1161/01.HYP.4.5.681
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Doctor insights on:
Lactase Insufficiency
What is a normal amount of lactase you can take?
Depends: The usual dose of lactase you need depends on why you're taking it. The recommended maximum is 18,000 units per dose up to 3 times per day. Most products have 3,000 to 9,000 units per tablet, so you'll need to know how much the product you're taking contains. If you need help figuring out the dose, do not hesitate to speak to a pharmacist or physician. ...Read more
Lactase (Definition)
Lactase is a digestive enzyme produced by the GI tract. It is needed to digest milk. Some loose the ability to produce lactase when he grow up. This ...Read more
Is it true that half of the population of the world are intolerant to lactase?
Adults: A majority of adults lose lactase and become intolerant to lactose. ...Read more
Please describe the most effective lactase tablet/product available?
Lactaid: Lactaid is the most commonly recommended digestive aid for lactose intolerance. Good luck! ...Read more
Do all people after the age of twenty stop producing lactase?
No: Some people are lactose intolerant, others have no problems at all. Lactase is the enzyme that breaks down the lactose typically found in dairy products. ...Read more
What is the definition or description of: lactase?
Milk digestion: Lactase is a digestive enzyme produced by the GI tract. It is needed to digest milk. Some loose the ability to produce lactase when he grow up. This is called lactose intolerance. ...Read more
My lactase dehydrogenase result is a 487, is that high?
LDH: Is LDH of 497 hi? Ask you lab for normal values as there is not international reference standard for this test and different Labs will have different normal values. So never ask us about a lab test without giving us the normal values 4 any test. ...Read more
What happens if lactase is taken by a lactose-intolerant person?
It helps.: Lactase is the enzyme needed to digest lactose, it is available over the counter and can help when taken with dairy products. For guidance on its appropriate use you should check with your doctor. ...Read more
Is there any advantage to taking lactase pills, even if you're not sure you're lactose intolerant yet?
Could be: If they make you feel better than i would use them regardless of what testing shows. ...Read more
Can i take lactase enzymes with prosac?
YES: There should be no interactions between lactase tablets and prozac. They can be safely taken in the same day. ...Read more
I am lactose intolerance (but depends on how much i consume). Would lactase pills be effective after symptoms show?
Lactose intolerance: Lactase (http://www.Drugs.Com/cdi/lactase.Html) is a great option for those who are lactose intolerant which as you've noted, depends upon what & how much you eat. Lactase won't work for everyone but it's worth a try. ...Read moreSee 1 more doctor answer
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Barton Bangla Brasserie - Preston
Address: 913 Garstang Road, Barton, Preston, Lancashire, PR3 5AB
Telephone: 01995 640236
Cuisine Type: Indian, Takeaway
Tell this Venue You Saw Them On Sugarvine
Reader Reviews
Excellent Indian restaurant. The host asks what type of curry you like and then comes up with a dish to suit. Ours were the perfect selection for us. The service was efficient and friendly, with the staff taking time out out to interact with our baby. We sat in the conservatory which was airy and bright. The best Indian in the area. N
I've been to the Bangla on a few occasions and it is the best Bangladeshi restaurant i have been to. the food is fantastic the tables are well set out and comfortable and the staff and service is 100%. I will be there again soon see you all then. Ronnie
literally just come back from Barton Bangla. It was AMAZING! food delicious, hot, tasty and well presented, premises beautiful but the best bit was the attentive staff who made it so enjoyable, I mentioned to one of the waters that we had never been before and were very impressed and upon paying the bill they offered us a complimentary drink. Will definitely be back. :-) Nicola Rowland
went to the barton bangla brasserie with my boyfriend as he had heard of it but never been there. the inside was really nicely decorated, we had a drink in the waiting area which was comfortable. the food was amazing, best Indian food i have ever eaten, good portion size and so delicious. the staff were friendly and i am definitely going back there Jenny BSee all Barton Bangla Brasserie Reviews.
Review Barton Bangla Brasserie, Preston
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* While offer lasts. Terms and conditions apply. You will receive your promotional code for your £50 discount with Virgin Wines by return email once the review has been approved for upload by our Site Administrator (this can take up up 72 hours).
Restaurants Near Barton Bangla Brasserie
Barton Grange Hotel, Garstang Road, Barton, Preston, Lancashire, PR3 5AA
01772 866135
Canalside, St Michael's Road, Bilsborrow, Garstang, Lancashire, PR3 0RS
01995 640010
Canalside, St Michael's Road, Bilsborrow, Garstang, Lancashire, PR3 0RS
01995 640010
Eaves Lane, Woodplumpton, Preston, Lancashire, PR4 0BJ
01772 690233
Brockholes Arms House, 113 Garstang Road, Claughton-on-Brock, Garstang, Lancashire, PR3 0PH
01995 640369
View all Restaurants in Preston
Latest Lancashire Deals
Lunch Menu: 3 courses plus coffee and petits fours, £29.50.
Fish and Chips Friday: Enjoy a complimentary glass of Prosecco or pot of tea with every fish and chips ordered on Fridays after 5pm.
Pre-Match or Post-Match 2 for 1 Offer: To Celebrate our Partnership and Support to Preston North End Football Club, all the Slice of Sicily Branches will offer on any match day, Pre-Match or Post- Match, with a valid ticket or season ticket a 2 for 1 offer on our Bistro Menu. Offer will be the same as written on the first page of menu.
Eat All You Can: Lunch Time Buffet: £8.50 (mon-thu) £8.99 (fri/sat) £3.99 (child between 3-6yrs) £4.99 (child between 7-10yrs). Evening Buffet: £13.99 (mon-thu) £14.99 (fri/sat) £6.50 (child between 3-6yrs) £7.50 (child between 7-10yrs). Sunday Buffet: £12.99 (Sun/bank holiday monday) £6.50 (child between 3-6yrs) £7.50 (child between 7-10yrs).


text: Home > Lifestyle > EnviroHealth > News 20 October 2006 10 dirtiest cities on earth Cancer, lung infections, and shortened life expectancy are among the threats facing people who live in the world's 10 most polluted cities, says a new report. 0 Start A Health24 blog » Follow Health24 on Facebook » Test Are you envirohealth savvy? » Ask EnviroHealth Expert » Blood Lions: Bred for the Bullet movie trailer The amazing mountains on Pluto Cancer, lung infections, and shortened life expectancy are among the threats facing people who live in the world's 10 most polluted cities, says a report released Wednesday by the Blacksmith Institute, an international environmental research group. "Living in a town with serious pollution is like living under a death sentence. If the damage does not come from immediate poisonings, then cancers, lung infections, mental retardation, are likely outcomes," the report said. It was compiled over seven years by a team of environmental and health experts, the Associated Press reported. The 10 most polluted cities are: Dzherzhinsk, Norilsk and Rudnaya Pristan in Russia; Linfen, China; Haina, Dominican Republic; Ranipet, India; Mayluu-Suu, Kyrgyzstan; La Oroya, Peru; Chernobyl, Ukraine; and Kabwe, Zambia. The report said most of the pollution in these cities comes from unregulated coal and lead mines or unrefined nuclear weapons manufacturing plants, the AP reported. In some cases, solutions could be as simple as removing contaminated soil and reducing dust levels, said David Hanrahan, chief of global operations at the Blacksmith Institute. – (HealthDayNews) Read more: Enviro health Centre Air pollution can kill October 2006 More in Lifestyle Qwaqwa residents battling severe water shortages More: EnviroHealthNews advertisement Read Health24's Comments Policy Comment on this story 0 comments Comments have been closed for this article. Logout Comment 0 characters remaining Share on Facebook Loading comments... Other news Medical SEE: 12 Things you didn't know about the brain Sex US STIs hit all-time high in 2015 Medical Human right-handedness might go back almost 2 million years Mental health Troubled childhood may boost bipolar risk Diet and nutrition Our genes may soon advise our food and lifestyle choices Lifestyle Which skin products are better, 'medical grade' or 'over-the-counter'? From our sponsors Keep an eye on your vision Which skin products are better, 'medical grade' or 'over-the-counter'? Win 1 of 6 R5000 cash prizes Win Skin Renewal voucher Live healthier Exercise benefits for seniors » Working out in the concrete jungle Even a little exercise may help prevent dementia Here's an unexpected way to boost your memory: running Seniors who exercise recover more quickly from injury or illness When sedentary older adults got into an exercise routine, it curbed their risk of suffering a disabling injury or illness and helped them recover if anything did happen to them. No relief for MS » Drug shows promise against MS in mouse study Vitamin D may slow multiple sclerosis Obesity in girls tied to higher MS risk Exercise may not lower women's risk of MS A Harvard study showed no evidence to support the idea that exercise lowers the risk of multiple sclerosis.


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Question about Acer Aspire 5100 Notebook
Hi! ok so i bought a display unit at circuit city today. i didnt even think that i would have to ask for a password to get into the vista. so now i cant even use my computer because i dont have the password. the store is closed, im not even sure if they would know the password. i dont have a system restore disc it didnt come with it. anything i can do to get into the computer/visa/windows?
Posted by macawgirl on
If you mean you cannot log on to windows, then press F8 while booting up, then this will take you into safe mode, select start windows in safe mode and then choose the administrator account and go into windows, make yourself a new user account, then delete the paswsorded one and restart the notebook.
Posted on Oct 09, 2007
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Eurosalou Hotel & Spa
This old-town hotel puts two sandy beaches and a world-class theme park within easy reach.
Set in Salou's old town, the Eurosalou is about a 10-minute walk from Llevant and Ponent beaches. It's also just a 10-minute bus ride from PortAventura theme park, one of the biggest in Europe.
At the hotel you'll find indoor and outdoor pools as well as a luxurious spa. And at night, guests can watch everything from flamenco to live music on the outdoor stage.
- Official Rating
- 1Building
- 7Floors
- 288Rooms
- 3Lifts
All Inclusive - Here's what you get
Full Board meals. Snacks 11.00-18.00. Ice-cream 11.00-19.00. Picnics - reserve by 19.30 the day before
Unlimited local alcoholic and non-alcoholic drinks 11.00-23.00. Mineral water, juices, soft drinks, local wine, local beer and sangria with meals.
Sports and Activities
All are included except where indicated.
Facilities► View all
Evening entertainment programme
A variety of shows and live performances for all the family to enjoy including an organist.
Outdoor pool
This is a family pool with a kids' section. Parasols, sunbeds and a shower area are provided. Please note, this pool closes at an earlier time of 6pm in the spring months.
Buffet Restaurant
For breakfast, lunch and dinner with themed evenings throughout the week.
Rooms ► View all
twin room with balcony
These twin rooms come complete with air-conditioning, satellite TV and a balcony.
family room with terrace
Simply styled in gentle tones, these family rooms include a terrace for some space outside. You'll als get air-conditioning, a double bedroom with an extra sofa-bed, plus a foldaway bed.
TripAdvisor Traveller Reviews Show more reviews »
Too many rules for all inclusive!
I have just returned from a 4 night stay in the Eurosalou on an all inclusive basis. After reading the reviews myself and 2 friends were feeling a little concerned but decided to make the most of it...it was okay. What left me most perplexed was the vast amount of procedures that guests have to follow, from having to wear wrist bands and show a key card for every single drink! Of which you can only order 3 at a time. Then you have to wait to be seated for every meal, wait to have a waiter take your drink order and then before you can leave you have to hand over your drinks bill to be processed. It's just all such a waste of precious holiday time, either it's all inclusive and you can have what you want or they should stop offering this option! I have never experienced an all inclusive which operates this way, it felt like they were trying to stop people having too much. Staff were also shameless at serving the Spanish first, regardless of who had been waiting longest, this was very frustrating as the service was slow at best. Food was ok, we used it 3 days out of 4, but very similar for all meals and nothing special. Pool was smaller than it looks and you have to hope for a good spot for your subbed, due to pool area being in and out of shade throughout the day, no one clearing rubbish or empty glasses either. Room would have been fine for 2 but was very snug for 3 beds. Reception staff are the only ones who smile and were helpful. Entertainment team have a hard job, seems they are expected to entertain with no budget or resources apart from a palm tree suit, they tried their best. Location was really good, the hotel is on a busyish road but beach only 10 mins walk, a few shops just across the road for basic needs. Barcelona 1.5 hour away, so can visit in a day, and transfer time only 20 mins! If you have already booked don't panic, you will have a nice time but just be prepared for some odd protocols. If you haven't booked consider looking at other nearby hotels in Salou that don't insist on crazy monitoring whilst you are on holiday. Sorry but I won't be back!More
Went here for 2 weeks with my daughter in law at the beginning of September. On arrival the hotel looked clean and the staff behind reception were really nice and friendly. We had to pay for the safe and upon leaving you got a deposit back. The fridge, which was very small was â¬42 for 14 nights. No deposit to pay. If you want tea, coffee, sugar then you have to pay to hire the kettle. Best to buy one from the shop on the other side of the street. The bedroom was below average. The wardrobe had 1 door on it. The bathroom could do with updating. The beds were comfortable and bigger than a single bed. The bedding had not been changed in the 14 nights. I told the rep a few times and it still was not changed. There was fluff under the bed and the mirrored wardrobe door and balcony door had handprints all over them. We were on the 5th floor with a pool view. Which was nice. The food was above average. it is only a 10 to 15 minute walk to the beach and all the shops. I would not stay there again, but for comfort it was ok. You get what you pay for. The spa is â¬7 for 4 hours, which has a pool, jacuzzi and sauna.More
Linda L, 187067
Great time!
Travelled as a couple for 2 weeks in Sept 2016. Had a great time at the hotel. Rooms were fine, large bathroom and nice cool Aircon. Always found food that I could eat at lunch and Dinner, though breakfast was a bit basic (only went 2/3 times). The pool was a decent enough size and never really had an issue getting loungers. The main plus were the entertainment team: Mike, Jo & Suzannah. They kept everyone entertained and active throughout our stay and had some real good laughs with them. They work hard, so if you're there join in as it makes the day much more fun for everyone! The Hotel is a 10 min walk to the beach, and 20/25 mins to the far end of the strip. Would definitely come back to this hotel! Kizunguzungu!!!More
Stephen H,
Don't waste your money
Firstly the hotel isn't big enough for the amount of guests it holds, the staff don't really bother speaking to you and appears the Spanish guests get privilege. I had to complain several times and I'm not a complainer, the food isn't great, we had hard peas and under cooked chicken and meat balls on separate occasions. The plates were chipped and dirty. I hired a safe but left my watch on the bed behind our suitcases as we was packing, came back and it was missing. They did a room check to see who entered our room and the only person was the cleaner. Manager says she trusts her staff but the evidence was obvious. Eurosalou and thomson have both brushed it under the carpet, manager refused to do a letter for our insurance. She reports no other incidents have been reported but the morning I was reporting it to the Thomson rep another family was also reporting an engagement ring go missing from there room our nextdoor neighbours also had money go missing and other reviewers on here have also said. There is a a big issue here and I do suspect the management is also part of it as that's why she brushed it off. I'd say avoid or lock everything in your safe and don't leave anything out by mistake as we did and I'm learning from it nowMore
OK for short break
On summary this hotel was ok for my 3 night hen trip. Good points - reception staff very helpful and friendly. (Other staff not rude but very busy and rushed). Room was clean, beds comfy. Public areas clean. Food plentiful. Bad points - pool very cold as hardly got the sun. Sunbathing area small for the size of the hotel and constant need to move sun bed to keep in the sun. After 2 hours there on our first day, couldn't be doing with that so we went to beach instead each day. toilets in bar /pool area were not of good standard - we would go back up to our room rather than use them! Food was average - not very varied from day to day. All inclusive was odd - had to show wristbands AND swipe room key each time, only 3 drinks allowed per order and finished at 11pm. As we went to beach every day due to the poor pool and terrace area we didn't get our money's worth really. If we'd been there longer I'd have felt really annoyed but for 3 dauto break it was ok and our 2 full days there were gorgeous and hot. Beach was 10-15 minute walk. Lovely sandy beach and clear sea. Hired beds from The Green Bar - 5⬠each plus 7⬠for parasol. Really genuine friendly guys there and fab cocktails! Loads to do on beach (paraseiling, banana boat,jet skis, pedalos). Old Town Salou has really nice clothes and gift shops - not just the usual tourist tat. House of Illusion magic show very good. Tapas bar (Goretti ) on seafront was tasty and good value.More
Kate P,
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CASIO MSG2010D-2V Owner's Manual
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How much off level is ok? My heads are pointed a tad up (facing the sky not the ground).
After all, the leveling should be done with a weighted car.
How much off level is ok? My heads are pointed a tad up (facing the sky not the ground).
After all, the leveling should be done with a weighted car.
There is really no way to quantify that. But it has been demonstrated repeatedly, at every meet I have attended, that even very minor variations in levelling make a significant difference.
As for weighting the car, I'm not sure that is an issue. The car is designed to settle equally, regardless of weight. And when you are hauling ballz down the highway, your front end is going to rise anyhow. Then there is the nose dip when you slam on the brakes too, which I theorise may contribute to some PT failures.
There has been some limited testing to check the nose-dive theory, and it seems to demonstrate that it is not a significant factor. But every car is different. Every set-up is different. And every laser encounter is different. Because of all those inconsistencies is exactly why it is important to keep your levelling consistent. It keeps your set-up optimised for the greatest number of encounters.
You're best off testing your setup. You can use some simple math to figure out just how far over your target your heads will be firing at typical laser encounter distances but that won't really tell you if they're effective or not.
Do most people actually use a level to level them or just by eye sight?
They come with levels, and that is the only way to do it. You absolutely cannot get it close enough by eyesight. It takes only a few degrees to totally screw it up.
The really hard part is getting them properly aligned. With most grilles being curved, you can't use a straight-edge across the front to do it with. And the curve in the grille creates an optical illusion that makes them look misaligned even when they are not, and vice versa.