Simvastatin Prevents Angiotensin II–Induced Cardiac Alteration and Oxidative Stress

Abstract

Abstract-The influence of the HMG-CoA reductase inhibitor simvastatin was assessed on the cardiovascular alterations and production of free radicals associated with chronic angiotensin II (Ang II) infusion. Simvastatin (60 mg/kg per day PO) or placebo were given concomitantly for 10 days in Sprague-Dawley rats infused with Ang II (200 ng/kg per minute SC, osmotic pump). In addition, simvastatin or placebo was also given in vehicle-infused rats. Tail-cuff pressure and albuminuria were measured before and at the end of the treatment period. Cardiac weight, carotid structure, production of reactive oxygen species (ROS, by chemiluminescence) by polymorphonuclear leukocytes and aortic wall as well as protein and lipid oxidation products were determined at the end of the study. Ang II increased tail-cuff pressure by 56Ϯ12 mm Hg and simvastatin blunted the development of hypertension by Ϸ70% (19Ϯ5 mm Hg). Increases in heart weight index and carotid cross-sectional area induced by Ang II were obliterated by simvastatin (3.18Ϯ0.09 versus 3.46Ϯ0.11 mg/g body wt and 0.125Ϯ0.010 versus 0.177Ϯ0.010 mm 2 , respectively). The Ang II-induced increases in leukocyte and aortic production of ROS as well as protein and lipid oxidation products were prevented by simvastatin. No effect of simvastatin was detected in non-Ang II-infused rats. These results indicate that simvastatin prevented the development of hypertension and cardiovascular hypertrophy together with inhibition of the induced angiotensin II production of ROS. Therefore, inhibition of HMG CoA reductase by statins may have a beneficial effect on cardiovascular alterations through its antioxidant action in experimental Ang II-dependent hypertension. A ngiotensin II (Ang II) exerts multiple effects on the cardiovascular system including hypertension and cardiovascular hypertrophy, and free radical production has been proposed as a mechanism participating in Ang II-induced cardiovascular alterations. 1 Through stimulation of its type 1 receptor, Ang II was shown to be associated with an overexpression of cytosolic proteins involved in the activation of the NAD(P)H oxidase of vascular endothelial cells, smooth muscle cells, and leukocytes. 2,3 In these cells, Ang II favors the production of reactive oxygen species (ROS) such as superoxide anions, hydrogen peroxide, and hydroxyl radicals. 2 Together with leukocyte adhesion and proliferation and migration of various cell types, these events may lead to phenotype transformation of the arterial wall and vascular hypertrophy.Experimental evidence and clinical studies strongly suggest that 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) reductase inhibitors (statins) might have antiatherosclerotic effects independent of low-density lipoprotein (LDL) cholesterol reduction. Among the pleiotropic effects of statins are inhibition of smooth muscle cell proliferation (except for pravastatin), 4 reduction of matrix metalloproteinase expression, 5 and stimulation of the antithrombotic system. 6,7 In addition, it has been shown that an inhibitor...

Simvastatin prevents large blood pressure variability induced aggravation of cardiac hypertrophy in hypertensive rats by inhibiting RhoA/Ras–ERK pathways

“…Second, simvastatin prevents cardiac hypertrophy in rats receiving angiotensin II infusion. 44 Statins downregulate AT1R expression in platelets and vascular smooth muscle cells. 45,46 Thus, simvastatin may prevent SAD-induced aggravation of hypertensive cardiac hypertrophy, at least in part, by inhibiting the angiotensin II-mediated mechanism.…”

Simvastatin Inhibits Leukocyte Accumulation and Vascular Permeability in the Retinas of Rats with Streptozotocin-Induced Diabetes

“…[1][2][3] Therefore, the ability of statins to inhibit ICAM-1 expression indicates that statins can attenuate leukocyte-endothelial cell interactions and the subsequent endothelial damage and tissue injury. Indeed, many studies have reported that statins can inhibit leukocyte-endothelial cell interactions in many conditions, such as thrombin-activated leukocyte-endothelial cell interactions, 47 angiotensin II-induced injury, 35,48 transient ischemic injury, 36,49 and Staphylococcus aureus ␣-toxin-induced inflammation. 14 These results provide the best evidence to support the view that statins can inhibit leukocyte-endothelial cell interactions independent of their lipid-lowering effect.…”

“…[33][34][35][36][47][48][49] These differences may derive from the diversity of the mechanisms of each model or duration of the drug administration. In addition, many studies with streptozotocin-induced diabetic animals were performed for a relatively short duration compared to chronic diabetes in human.…”

Cardiorenal abnormalities associated with high sodium intake: correction by spironolactone in rats

“…Values of four clearance measurements were averaged to provide a single value for glomerular filtration rate (GFR) and effective renal plasma flow. Urinary excretion of albumin was determined by immuno-nephelemetric method (3).…”