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M-005 CARDIOPROTECTIVE MECHANISMS OF RHO-KINASE INHIBITION VIA ANTI-OXIDATIVE STRESS IN PRESSURE OVERLOAD HEART IN RATS

Objectives Hypertrophic growth of the myocardium is noted in most forms of left ventricular dysfunction, and may be related to the fatal cardiovascular events, such as hypertension. Rho kinas inhibition could improve the left ventricular dysfunction. Impaired counterbalance between endothelin-1 (ET-1), and endothelial nitric oxide synthesis (eNOS) contributes to the progression of heart failure. In addition, it was reported that ET-1 could increase the expression of Rho kinase pathway via the oxidative stress. We examined whether Rho-kinase ameliorates left ventricular dysfunction and myocardial remodeling and assessed potential mechanisms for these actions in ascending aorta-banded rats. Methods and Results Starting 1 day and 29 days after ascending aorta banding, banded rats were treated with fasudil of 30 mg/kg/day or vehicle for 28 days and 14 days, respectively, in either early and late treated rats. Subsequently, in both treated rats, fasudil versus vehicle markedly attenuated BNPs level in left ventricles and plasma and the mean left atrial pressure and left ventricular hypertrophy, and reversed myocyte cross section area, interstitial fibrosis and perivascular fibrosis, as well as suppressed up-regulations of Rho-kinase I, Rho-kinase II, ET-1, and NADPH p47phox, p67phox in left ventricle, increases of thiobarbituric acid-reacting substances (TBARS) and DHE fluorescence staining in LV. Moreover, fasudil could increases the down-regulation of NO-cGMP pathway in both treated rats. Conclusions Long term treatment with the Rho kinase inhibitor fasudil improved LV dysfunction and remodeling by ameliorating the increases in the LV gene expression of ET-1, BNP, Rho kinase and Nox2-derived subunit in the aorta-banded rats. It inferred that antagonism between ROS and NO-cGMP at least contribute to the cardioprotective effect by Fasudil. Further translational study in human is needed to substantiate the findings.