Pitavastatin, an HMG-CoA Reductase Inhibitor, Exerts eNOS-Independent Protective Actions Against Angiotensin II–Induced Cardiovascular Remodeling and Renal Insufficiency

Abstract

Abstract-Angiotensin II (Ang II) plays a pivotal role in cardiovascular remodeling leading to hypertension, myocardial infarction, and stroke. Pitavastatin, an HMG-CoA reductase inihibitor, is known to have pleiotropic actions against the development of cardiovascular remodeling. The objectives of this study were to clarify the beneficial effects as well as the mechanism of action of pitavastatin against Ang II-induced organ damage. C57BL6/J mice at 10 weeks of age were infused with Ang II for 2 weeks and were simultaneously administered pitavastatin or a vehicle. Pitavastatin treatment improved Ang II-induced left ventricular hypertrophy and diastolic dysfunction and attenuated enhancement of cardiac fibrosis, cardiomyocyte hypertrophy, coronary perivascular fibrosis, and medial thickening. Ang II-induced oxidative stress, cardiac TGF␤-1 expression, and Smad 2/3 phosphorylation were all attenuated by pitavastatin treatment. Pitavastatin also reduced Ang II-induced cardiac remodeling and diastolic dysfunction in eNOS Ϫ/Ϫ mice as in wild-type mice. In eNOS Ϫ/Ϫ mice, the Ang II-induced cardiac oxidative stress and TGF-␤-Smad 2/3 signaling pathway were enhanced, and pitavastatin treatment attenuated the enhanced oxidative stress and the signaling pathway. Moreover, pitavastatin treatment reduced the high mortality rate and improved renal insufficiency in Ang II-treated eNOS Ϫ/Ϫ mice, with suppression of glomerular oxidative stress and TGF-␤-Smad 2/3 signaling pathway. In conclusion, pitavastatin exerts eNOS-independent protective actions against Ang II-induced cardiovascular remodeling and renal insufficiency through inhibition of the TGF-␤-Smad 2/3 signaling pathway by suppression of oxidative stress. Key Words: angiotensin II Ⅲ pitavastatin Ⅲ eNOS Ⅲ cardiorenal insufficiency A ccumulating evidence indicates that vascular wall inflammation plays a key role in the pathogenesis of vascular diseases and atherosclerotic processes, and angiotensin II (Ang II), a key effector of the renin-angiotensin system (RAS), plays a central role in the regulation of vascular tone, blood pressure (BP), and electrolyte homeostasis. 1 Ang II induces inflammation through BP-dependent and -independent mechanisms, and Ang II accelerates cardiovascular remodeling through enhanced oxidative stress, 1 vascular permeability, 2 leukocyte infiltration, 3-5 and tissue remodeling. 6 Because numerous clinical studies have shown that an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) prevent cardiovascular events and remodeling, 7-10 blockade of the RAS system is one of the major strategies for treatment of cardiovascular diseases.In addition to ACE inhibitors and ARBs, it has been shown that statins (3-hydroxy-3-methylglutaryl coenzyme A [HMGCoA] reductase inhibitors) are effective in preventing cardiovascular events 11-14 and ameliorating endothelial dysfunction. 15 These effects of statins cannot be explained merely by their lipid-lowering effects. 16 -18 In fact, statins have been reported to have ...

Activation of TGF-β Receptors and Smad Proteins by Atorvastatin is Related to Reduced Atherogenesis in ApoE/LDLR Double Knockout Mice

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Atorvastatin Prevents Angiotensin II–Induced Vascular Remodeling and Oxidative Stress

“…[17][18][19][20]22 However, less information is available about the effect of statins on the structural alterations of resistance arteries. Pitavastatin prevented the increase in media thickening of transversal sections from mouse coronary arteries after chronic Ang II infusion.…”

“…10 Moreover, several studies have shown that statins decrease blood pressure in variable degrees both in humans [11][12][13][14] and in experimental models, 15,16 although a lack of effect of statins on blood pressure levels has also been described. [17][18][19] Most of the benefits of statin therapy are attributable to the lowering of serum cholesterol levels. However, by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins can also inhibit the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, eg, Rho and Rac.…”

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