 dysregulation of their catabolism can affect glucose metabolism through the suppression of the pyruvate dehydrogenase complex and lead to cardiac ischemic injury (41).
Thus, BCAAs may also impact atherosclerosis prevention and offer a novel therapeutic strategy for certain individuals at risk of coronary events (37). ICs are impaired during atherosclerotic formation, and such aberrations of normal functioning correlate with the levels of specific AAs. AAs are fundamental elements for protein metabolism and participate in different cellular mechanisms for energy generation (63). Other AAs are indirectly associated with atherosclerosis as they play essential roles in vascular functioning; for example, L-Arg is involved in NO synthesis (64,65). On the other hand, despite such essential roles for some AAs, elevated levels of BCAAs can lead to pathological conditions, including neurological disorders and cardiomyopathy (66). In this review, we summarize the recent knowledge related to the role of AAs, including the BCAAs, Tryptophan (Trp), L-Arg, Taurine (Tau), Cysteine (Cys), Homoarginine (h-Arg) and Gly in the development and progression of atherosclerosis and atherosclerosis-related CVDs.

BCAAs Catabolism
Val, Leu, and Ile are essential BCAAs vital for the growth and functioning of cells and organs. They differ in their sidechain properties (e.g., hydrophobicity and conformation). The BCAAs constitute nearly 40% of all the AAs in the body (67). They represent about 35% of the essential AAs found in mammalian proteins (68). Leu stimulates myofibrillar protein synthesis (69,70). In the presence of lowered glucose, Leu, and its non-metabolizable analog, 2-aminobicyclo (2, 2, 1) heptane-2-carboxylic acid stimulate insulin secretion from the β cells of the pancreas (71). There is a strong requirement of Leu during the synthesis of sterols in adipose and muscle tissue (72). Approximately 60% of Leu is metabolized after several hours, of which about 5% is converted to β-hydroxy β-methylbutyric acid (73), and 40% is converted to acetylcoenzyme A (CoA) (74), which is used for the synthesis of other compounds. Catabolism of Leu is controlled by the enzymes, branched-chain amino acid aminotransferase (BCAT), and branched-chain α-ketoacid dehydrogenase (BCKD) to produce isovaleryl-CoA (75). Isovaleryl-CoA is further processed by the isovaleryl-CoA dehydrogenase and converted to 3-methylcrotonyl-CoA, which is used in the synthesis of acetyl-CoA and acetoacetate by the enzymes 3-methylcrotonyl-CoA carboxylase, 3-methylglutaconic-CoA hydratase and 3-hydroxy-3-methylglutaryl-CoA lyase (Figure 1). Following transamination, Ile is converted into tiglyl-CoA, 2-methyl-3-hydroxybutyryl-CoA and 2-methylacetoacetyl-CoA. The latter is further converted to propionyl-CoA (a glucogenic precursor) and acetyl-CoA, which enter into the tricarboxylic acid cycle (Figure 1). Familial deficiency of the 2-methyl-3hydroxybutyryl-CoA dehydrogenase enzyme causes progressive infantile neurodegeneration (76). Catabolism of Val starts with the transamination process, which is catalyzed by BCAT, which then through the action of BCKD produces isobutyryl-CoA, which is successively converted into propionyl-CoA and methylmalonyl-CoA. The latter compound enters into the tricarboxylic acid cycle (77) (Figure 1). Val decomposition products may act as signaling molecules. The only metabolite of BCAAs that does not have a covalent attachment to CoA is 3-hydroxyisobutyric acid (3-HIB), which can easily leave the mitochondrial matrix. The 3-HIB metabolite is synthesized within muscle; the surrounding plasma concentrations of 3-HIB typically range between 30 and 50 µM (78). Secreted 3-HIB acts as a paracrine signal acting on surrounding microvascular ECs, where it promotes the uptake of fatty acids and lipid accumulation in the muscle and can contribute to the development of insulin resistance (IR) in mice (78).

The Role of BCAAs in Atherosclerosis
Alterations in the levels of BCAAs are associated with disorders, including renal failure, atherosclerosis, and cancer (79). Specifically, after circulating BCAAs were demonstrated to correlate with increased risk for cardiovascular events and IR, Mels et al. assessed whether BCAA levels are associated with carotid intima-media thickness (cIMT) under hyperglycaemic conditions (80). Using regression analyses, they determined that an independent correlation exists between BCAAs and cIMT in individuals with high HbA1c levels and suggested that cardiovascular deterioration possibly accompanies hyperglycemia (80). Also, Yang et al. investigated whether AAs could be used to identify subclinical atherosclerosis subjects at risk of developing coronary artery disease (CAD) caused by atherosclerosis, as BCAA levels had previously been shown to correlate with atherogenic dyslipidemia (40). Based on carotid artery images and BCAA serum levels, they determined a significant and independent positive correlation between BCAAs (Val, Ile, and Leu) and increased cIMT (40). Identifying such to the elevated levels of circulating BCAAs observed, rather than changes in BCAA intake (82,83). Several studies have shown an association between BCAAs, their metabolites, and CAD (84). For example, mass spectrometric analysis of plasma samples taken from almost 2,000 CVD patients showed 63 differentially synthesized metabolites and further suggested that the levels of some BCAAs and their metabolites are related to the severity of CAD (84). The increase in plasma BCAA levels in CAD may be due to lower BCAA uptake and usage by muscles and other tissue (85), or lowered activity of the critical enzyme BCKD complex (BCKDC) responsible for the degradation of all BCAAs in animals (86,87). The accumulation of BCKDC has been linked to heart failure via direct perturbation of respiration and increased ROS synthesis within the mitochondria (88). Defects in BCAA catabolism can more widely affect metabolism in murine failing hearts through alterations in Krupel-like factor-15 (89). Supplementation with BCAAs can decrease heart muscle injury and ameliorate hematological parameters in rats during endurance exercises (90). Contrary to this, several prospective metabolomic studies of incident coronary heart disease (CHD), CAD, and MI failed to identify associations of any BCAAs with CVD (91)(92)(93). Supplementation with BCAAs at a dose of 1.5 mg/g body weight/day in drinking water preserves skeletal muscle weight and ameliorates HF in a rat model (94). Also, Leu (1.5% w/v) supplementation in ApoE −/− mice reduces the growth of atherosclerotic plaques via reduced inflammation and an improvement in the lipid profile (increased high-density lipoprotein cholesterol (HDLc) and reduced LDL) (26). Leu (1.3% dietary protein-energy intake) was inversely associated with arterial stiffness and atherosclerosis in females (95). Leu supplementation in humans, at a dose of 5 g/day for 3 weeks, modifies lipid metabolism in macrophages while simultaneously enhancing mitochondrial respiration, which may offer a potential strategy to attenuate atherosclerosis development in humans (96). Regarding cardiovascular risk, there are positive and negative atherogenic roles of BCAAs. Certain BCAAs, in particular Leu, are well-known for their attenuative effects on macrophage lipid accumulation and subsequent formation of foam cells in blood vessel walls. This role is related to the decrease in cholesterol and triglyceride macrophage content. A decrease in cholesterol content is obtained through reduced verylow-density lipoprotein (VLDL) uptake, inhibition of cholesterol synthesis, and cholesterol cell efflux. On the other hand, a decrease in cellular triglycerides results from inhibition of the enzyme, diacylglycerol acyltransferase-1, which catalyzes the synthesis of triglycerides in macrophages. One particular study observed increased levels of circulating BCAAs in CVD, diabetes, IR, obesity, and healthy individuals, independently of body mass index (97). Metabolic status is the key element that determines whether increased levels of a particular BCAA has a positive or negative influence on CVD risk (97,98). In this regard, it is known that some stimuli can impact tissues involved in BCAA clearance, such as brown adipose tissue (BAT), a well-known thermogenic (and BCAA catabolic) organ. Cold exposure influences BAT to promote the oxidation of BCAAs to obtain enough energy for thermogenesis produced by mitochondria, thus promoting systemic BCAA clearance.
Cold exposure additionally affects lipid catabolism but does not influence glycaemia. Brown adipocytes take up and transport BCAAs via mitochondrial BCAT1 and Solute Carrier Family 25 Member 44 gene (SLC25A44). Defects in these processes have been shown to impair the thermogenesis and influence BCAA systemic clearance leading to obesity and conditions linked to IR (98). Collectively, BCAAs appear to represent important indicators of CVD risk, and further work is required to fully understand their involvement in such pathologies.

Trp Catabolism
Trp is an AA acquired through the diet because the human body is unable to synthesize it. Once absorbed through the intestine into theportal blood, 85-90% of Trp is transported in the plasma bound to serum albumin, while only 10-15% of the total plasma Trp is in the free form (99). The metabolic pathway responsible for approximately 90% of Trp catabolism is the kynurenine synthesis pathway (