Published online before print October 25, 2007, doi: 10.1161/CIRCRESAHA.107.163493
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Submitted on May 2, 2007
Revised on October 2, 2007
Accepted on October 17, 2007
Pitavastatin, an HMG-CoA Reductase Inhibitor, Exerts eNOS-Independent Protective Actions Against Angiotensin II–Induced Cardiovascular Remodeling and Renal Insufficiency
Shusuke Yagi ;
From the Department of Medicine and Bioregulatory Sciences (S.Y., K.A., Y.I., Y.S., S.Y., T.I., T.I., K.I., H.A., M.A., T.M.), The University of Tokushima Graduate School of Health Biosciences, Japan; and the 21st Century Center of Excellence Program of the University of Tokushima (Y.I., T.M.), Japan.
* To whom correspondence should be addressed. E-mail: aihara{at}clin.med.tokushima-u.ac.jp.
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-/- mice as in wild-type mice. In eNOS-/- 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-/- 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 • pitavastatin • eNOS • cardiorenal insufficiency
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