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Cardiovascular Research 2006 69(3):726-735; doi:10.1016/j.cardiores.2005.08.001
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Copyright © 2005, European Society of Cardiology

Pravastatin increases survival and suppresses an increase in myocardial matrix metalloproteinase activity in a rat model of heart failure

Sahoko Ichiharaa,b,c, Akiko Nodad, Kohzo Nagatad, Koji Obataa, Jinglan Xua, Gaku Ichiharab, Shinji Oikawae, Shosuke Kawanishie, Yoshiji Yamadac and Mitsuhiro Yokotaa,*

aDepartment of Cardiovascular Genome Science, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
bSocial Life Science, Nagoya University Graduate School of Medicine, Nagoya, Japan
cDepartment of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, Japan
dDepartment of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan
eDepartment of Environmental and Molecular Medicine, Mie University School of Medicine, Tsu, Japan

* Corresponding author. Tel.: +81 52 744 2609; fax: +81 52 744 2977. Email address: myokota{at}med.nagoya-u.ac.jp

Objectives: Oxidative stress is implicated in the pathogenesis of heart failure and affects the activity of matrix metalloproteinases (MMPs). We have now investigated the role of MMPs and their tissue inhibitors (TIMPs) in the transition from compensated left ventricular (LV) hypertrophy to heart failure as well as the effects of pravastatin on this transition in a rat model.

Methods: Dahl salt-sensitive rats were fed a high-salt (8% NaCl) diet and treated with pravastatin (50 or 100 mg/kg per day) or vehicle from 7 weeks of age.

Results: Pravastatin did not attenuate LV hypertrophy apparent at 12 or 18 weeks of age. However, the high dose of this drug markedly improved indices of diastolic function (early diastolic myocardial velocity) and systolic function (LV fractional shortening) at 18 weeks of age and increased the survival rate. It also prevented a decrease in the ratio of reduced to oxidized glutathione and an increase in NADPH oxidase activity in the left ventricle induced by the high-salt diet. The activities of MMP2 and MMP9 and the abundance of TIMP1 and TIMP2 in LV tissue were increased at 18 weeks of age, and pravastatin also prevented these changes.

Conclusion: Although pravastatin did not attenuate LV hypertrophy, it prevented the transition from compensated hypertrophy to heart failure in this rat model. This effect of pravastatin may result from a reduction both in the level of oxidative stress and in MMP activity in the heart.

KEYWORDS Heart failure; Matrix metalloproteinases; NAD(P)H-oxidase; Oxidative stress; Statins

Time for primary review 34 days


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