Simvastatin Prevents Load-Induced Protein Tyrosine Nitration in Overloaded Hearts

Abstract

Abstract-Hydroxymethylglutaryl-coenzyme A reductase inhibitors prevent load-induced left ventricular hypertrophy (LVH). Whether this effect is related to antioxidant properties of this class of drugs is poorly understood. The aim of the present report was to evaluate the regulation of nitrotyrosine production during the development of load-induced LVH and the effect of simvastatin treatment in this process. Rats were subjected to aortic constriction up to 15 days. LVH was evaluated by left/right ventricle mass ratio. Myocardial content of nitrotyrosine, nitric oxide synthase (NOS) isoforms, and phagocyte-type NAD(P)H-oxidase subunits (p67-phox and p22-phox) were analyzed by immunoblotting and immunohistochemistry assays. Another group of rats received treatment with either simvastatin or placebo for 15 days after the onset of pressure overload, and their hearts were also studied. Myocardial nitrotyrosine content was increased from 3 to 15 days of pressure overload in regions of cardiac myocytes in close apposition to myocardial stroma during LVH. Neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS) isoforms had their expression increased in coronary vessels (nNOS and iNOS) and in myocardial stroma (eNOS) from day 3 to day 7 of aortic constriction. However, p67-phox and p22-phox expression was increased in cells of myocardial stroma in parallel to augmented myocardial nitrotyrosine content. Simvastatin treatment inhibited the increases in myocardial nitrotyrosine content and in p67-phox and p22-phox expression, and significantly reduced LVH. In conclusion, antioxidant properties of simvastatin might play a role in myocardial remodeling induced by pressure overload.

Atorvastatin Slows the Progression of Cardiac Remodeling in Mice with Pressure Overload and Inhibits Epidermal Growth Factor Receptor Activation

“…Interestingly, a recent study reported that GPCR modification could inhibit cardiac hypertrophy via reduction of EGFR transactivation (33). The present study showed that atorvastatin could substantially decrease cardiac remodeling, as indicated by a reduction of LV wall thickness and LV dimensions as well as improvement of myocyte hypertrophy and perivascular fibrosis, findings that are consistent with the results of a recent pilot clinical trial (4) and several previous experimental studies (28,29,34). However, no study has yet examined whether or not statins can inhibit EGFR transactivation.…”

Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload

“…A similar observation of increased nitrotyrosine staining has been made in animals subjected to chronic aldosterone infusion 12 or pressure overload due to aortic constriction. 42 Although our data do not allow us to determine the precise oxidant species, they are consistent with increases in reactive oxygen species (eg, superoxide), reactive nitrogen species (eg, nitric oxide), or both. Superoxide and nitric oxide may react chemically to yield peroxynitrite, a potent oxidant that is capable of causing tyrosine nitration.…”

Is Cardiac Hypertrophy in Spontaneously Hypertensive Rats the Cause or the Consequence of Oxidative Stress?

“…On the other hand, lipid peroxidation and oxidative modification of proteins by reactive nitrogen species such as peroxynitrite-a product of the reaction between superoxide (O2 −˙) and nitric oxide (NO)-have been implicated in the pathogenesis of cardiac hypertrophy and normal aging (13,14).…”