Effects Of Atorvastatin On Cardiovascular Remodeling In Spontaneously Hypertensive Rats

Hypertension mainly causes higher mortality of cardiovascular diseases. Hypertension is always accompanied with artery wall thickening, left ventricular hypertrophy (LVH) and cardiac fibrosis. These structural changes in heart and blood vessels are known as cardiovascular remodeling. Vascular remodeling accounts for the hypertensive target organs damage, and the heart structural alterations by long-overloading pressure from hypertension are responsible for the increasing morbidity and mortality of cardiac events. Vascular remodeling mainly concerns proliferation, hypertrophy and migration of vascular smooth muscle cell(VSMC), and elevated content of connective tissue. LVH is one of the major complications of essential hypertension, mainly caused by cardiac myocyte proliferation, hypertrophy, interstitial fibrosis and cardiac myocyte apoptosis. Therefore, treatment of hypertension shall aim not only at the optimal control of blood pressure, but also the prevention of the cardiovascular remodeling.Essential hypertension relates closely to blood vessel endothelial disorder. Elevated peripheral vascular resistance is characteristic of hypertension, and blood vessel system is not only regulator of peripheral vascular resistance, also target of hypertension. Blood vessel endothelial cells excited by blood stream shear stress and pulsation, ischemia, hypoxia and more produced oxygen-derived free radicals, and etc, cause endothelial dysfunction. What's more, endothelial dysfunction causes dysregulation between various kinds of blood vessel activity materials and growth factors, with more vasoconstriction factors such as endothelin(ET) and angiotensin(Ang II) and less vasodilatation factors such as nitrogen monoxide (NO) releasing, resulting in the changes of structure and function in blood vessel.It was reported that vascular remodeling was associated with the imbalance between VSMC growth and apoptosis. However, cell cycle is negatively regulated by cyclin-dependent kinase inhibitor (CDKI) such as p27. p27 can bind to and inhibit the activity of cyclin-dependent kinases(CDK) thereby prevent cell cycle progression of late GI to S-phase transition. RhoA is activated by signal transduction pathways involved in VSMC growth and differentiation through reduced expression of p27, and even facilitating more VSMC proliferation and hypertrophy than VSMC apoptosis, and then resulting in increases in artery wall thickness.Mevalonate (Mev) pathway plays a role in cell growth. Mev is intracellularly synthesized from 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), and this process is catalyzed by HMG-CoA reductase, the rate-limiting enzyme in this pathway. Mev metabolism yields a series of isoprenoids that are vital for the posttranslational isoprenylation of some proteins such as Ras and Rho. RhoA is activated by signal transduction pathways involved in VSMC growth and differentiation, and increases in RhoA expression contribute to the enhanced vascular responsiveness in hypertension. And the activated Ras, a cellular signal transduction protein, has been linked to proliferation, hypertrophy of VSMC and cardiac myocyte hypertrophy. Recent study shows that HMG-CoA reductase inhibitor-statins such as atorvastatin have dual effects: inhibiting cell proliferation and migration, facilitating cell apoptosis, associated with the retardation of cycling cells in the G1 and G2/M compartments, and ameliorating endothelial function, independent of the main cholesterol-lowering effects.Researches in the mechanisms of statins independent of cholesterol-lowering effects suggest that atorvastatin may have helpful effects on improving cardiovascular remodeling in hypertension. The mechanisms by which atorvastatin affected vascular remodeling could be explained as follow. Firstly, atorvastatin could improve endothelial function by recovering the balance between NO and ET, Ang II; Secondly, atorvastatin could reverse the state of imbalance between growth andapoptosis of VSMC during the development of vascular remodeling,...