High-Dose Atorvastatin Improves Hypercholesterolemic Coronary Endothelial Dysfunction Without Improving the Angiogenic Response

Boodhwani, Munir; Nakai, Y.; Voisine, Pierre; Feng, Jun; Li, Jian; Mieno, Shigetoshi; Ramlawi, Basel; Bianchi, Cesario; Laham, Roger J.; Sellke, Frank W.

doi:10.1161/circulationaha.105.000356

Cited by 35 publications

(45 citation statements)

References 34 publications

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“…Our experiments suggested that epithelial cell proliferation and reversal of emphysema were observed dose-dependently within the range of 0 -5 mg⅐kg Ϫ1 ⅐day Ϫ1 of SS. Although decreased plasma VEGF concentrations in the late-phase model may reflect the inhibitory effects of high-dose statins on endothelial functions as previously reported (9,35), BALF VEGF levels tended to increase and emphysematous changes were significantly improved by treatment with the medium dose of SS (1 mg⅐kg Ϫ1 ⅐day Ϫ1 ), as a consequence, in this protocol. Since the low and medium doses of SS (0.2 and 1 mg⅐kg Ϫ1 ⅐day Ϫ1 , respectively) correspond to those in patients with hyperlipidemia, our findings related to its dosedependent favorable effects on emphysema may promise further clinical implication.…”

Section: Discussionsupporting

confidence: 63%

Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice

Takahashi¹,

Nakamura²,

Seki³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Besides lowering cholesterol, statins exert multiple effects, such as anti-inflammatory activity and improvement of endothelial cell function. We examined whether simvastatin (SS) protects against the development of elastase-induced pulmonary emphysema in mice by using mean linear intercepts of alveoli (Lm) as a morphometric parameter of emphysema. After injection of intratracheal elastase on day 0, C57BL/6 mice were treated daily with SS (SS+ group) or PBS (SS− group) for 2 wk. A 21% decrease in Lm on day 7 was observed in the SS+ group vs. the SS− group. Anti-inflammatory effects of SS were observed as a decrease in percentage of neutrophils up to day 3, and in hydroxyproline concentration on day 3, in bronchoalveolar lavage fluid (BALF). SS also increased the number of proliferating cell nuclear antigen (PCNA)-positive alveolar epithelial cells between days 3 and 14. To confirm the role of statins in promoting proliferation of alveolar cells, mice were treated with SS (SS+) vs. PBS (SS−) for 12 days, starting 3 wk after elastase administration. After SS treatment, Lm decreased by 52% and PCNA-positive alveolar epithelial cells increased compared with the SS− group. Concentrations of vascular endothelial growth factor in BALF and endothelial nitric oxide synthase protein expression in pulmonary vessels tended to be higher in the SS+ group vs. the SS− group in this protocol. In conclusion, SS inhibited the development of elastase-induced pulmonary emphysema in mice. This therapeutic effect was due not only to anti-inflammation but also to the promotion of alveolar epithelial cell regeneration, partly mediated by restoring endothelial cell functions.

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Section: Discussionsupporting

confidence: 63%

Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice

Takahashi¹,

Nakamura²,

Seki³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…It appears that low doses induce proangiogenic effects through Akt activation, which leads to eNOS phosphorylation and NO production [16]. Boodhwani et al has shown that atorvastatin at higher doses improves coronary endothelial dysfunction in hypercholesterolemic animals without improving angiogenic response [17]. Statins have also been shown to have dose dependent effects on VEGF expression [18].…”

Section: Discussionmentioning

confidence: 99%

Statin and resveratrol in combination induces cardioprotection against myocardial infarction in hypercholesterolemic rat

Penumathsa

Thirunavukkarasu

Koneru

et al. 2007

Journal of Molecular and Cellular Cardiology

152

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Hypercholesterolemia (HC) is a common health problem that significantly increases risk of cardiovascular disease. Both statin (S) and resveratrol (R) demonstrated cardioprotection through nitric oxide dependent mechanism. Therefore the present study was undertaken to determine whether combination therapy with statin and resveratrol are more cardioprotective than individual treatment groups in ischemic rat heart model. The rats were fed rats with 2% high cholesterol diet and after 8 weeks of high cholesterol diet the animals were treated with statin (1mg/kg bw/day) and resveratrol (20mg/kg bw/day) for 2 weeks. The rats were assigned to: 1) Control (C) 2) HC 3) HCR 4) HCS and 5) HCRS. The hearts, subjected to 30 min global ischemia followed by 120 min reperfusion were used as experimental model. The left ventricular functional recovery (+dp/dt) was found to be significantly better in the HCRS (1926±43), HCR (1556±65) and HCS (1635±40) compared to HC group (1127±16). The infarct size in the HCRS, HCS and HCR groups were 37±3.6, 43±3.3 and 44 ±4.2 respectively compared to 53±4.6 in HC. The lipid level was found to be decreased in all the treatment groups when compared to HC more significantly in HCS and HCRS groups when compared to HCR. Increased phosphorylation of Akt and eNOS was also observed in all the treatment groups resulting in decreased extent of cardiomyocyte apoptosis but the extent of reduction in apoptosis was more significant in HCRS group compared to all other groups. In-vivo rat myocardial infarction (MI) model subjected to one week of permanent left descending coronary artery (LAD) occlusion documented increased capillary density in HCR and HCRS treated group when compared to HCS treatment group. We also documented increased β-catenin translocation and increased VEGF mRNA expression in all treatment groups. Thus, we conclude that the acute as well as chronic protection afforded by combination treatment with statin and resveratrol may be due to pro-angiogenic, antihyperlipidemic and anti-apoptotic effects and long term effects may be caused by increased neovascularization of the MI zone leading to less ventricular remodeling.

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“…Statins increase nitric oxide bioavailability through the activation of Akt (71,72,77,78). Akt induces endothelial nitrous oxide synthase production and enhances its activity (71,72,77,78).…”

Section: Lipid-lowering Agentsmentioning

confidence: 99%

The Effects of Medications on Myocardial Perfusion

Zoghbi

Dorfman

Iskandrian

2008

Journal of the American College of Cardiology

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Antianginal and lipid-lowering medications may modify the results of stress myocardial perfusion imaging. Several studies have shown the beneficial potential of these agents in suppressing myocardial ischemia in patients with known coronary artery disease. The effects of nitrates, calcium-channel blockers, beta-blockers, and statins on myocardial perfusion imaging are likely attributable to changes in myocardial blood flow and myocardial oxygen supply-demand ratio. This comprehensive review examines relevant experimental and clinical published data. Technical issues in image interpretation specific to myocardial perfusion imaging and implications of use of cardiac medications to results of myocardial perfusion imaging are discussed.

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High-Dose Atorvastatin Improves Hypercholesterolemic Coronary Endothelial Dysfunction Without Improving the Angiogenic Response

Cited by 35 publications

References 34 publications

Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice

Reversal of elastase-induced pulmonary emphysema and promotion of alveolar epithelial cell proliferation by simvastatin in mice

Statin and resveratrol in combination induces cardioprotection against myocardial infarction in hypercholesterolemic rat

The Effects of Medications on Myocardial Perfusion

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