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

• Published in: Circulation research 2008-01, Vol.102 (1), p.68-76
• Main Authors: Yagi, Shusuke, Aihara, Ken-ichi, Ikeda, Yasumasa, Sumitomo, Yuka, Yoshida, Sumiko, Ise, Takayuki, Iwase, Takashi, Ishikawa, Kazue, Azuma, Hiroyuki, Akaike, Masashi, Matsumoto, Toshio
• Format: Article
• Language: English
• Subjects: Angiotensin II - administration & dosage; Angiotensin II - pharmacology; Animals; Biological and medical sciences; Cardiotonic Agents - pharmacology; Cardiotonic Agents - therapeutic use; Fundamental and applied biological sciences. Psychology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hypertrophy, Left Ventricular - prevention & control; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Nitric Oxide Synthase Type III; Oxidative Stress; Quinolines - pharmacology; Quinolines - therapeutic use; Renal failure; Renal Insufficiency - prevention & control; Signal Transduction; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Transforming Growth Factor beta; Ventricular Remodeling; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.107.163493

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 TGFβ-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-β–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-β-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-β-Smad 2/3 signaling pathway by suppression of oxidative stress.