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Published on: July 14, 2021
Pravastatin attenuates left ventricular remodeling and diastolic dysfunction in angiotensin II-induced hypertensive
Zhujie Xu1, Hiroshi Okamoto, Masatoshi Akino
1Department of Cardiovascular Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Insights
Pravastatin improved diastolic dysfunction and cardiac remodeling in mice, independent of cholesterol levels. These pleiotropic effects suggest statins may benefit patients with diastolic heart failure (DHF).
Area of Science:
- Cardiology
- Pharmacology
Background:
- Diastolic dysfunction is common in heart failure patients with preserved ejection fraction.
- Limited therapeutic options exist for diastolic heart failure (DHF).
- Statins' effects on cardiac remodeling and survival in DHF warrant mechanistic investigation.
Purpose of the Study:
- To investigate the cardioprotective mechanisms of statins in a mouse model of diastolic heart failure.
- To determine if statin benefits in DHF are cholesterol-dependent or mediated by pleiotropic effects.
Main Methods:
- Angiotensin II infusion in mice to induce cardiac remodeling and fibrosis.
- Treatment with pravastatin, a statin, at doses that do not affect cholesterol or blood pressure.
- Assessment of cardiac function, hypertrophy, fibrosis, and gene expression.
Main Results:
- Pravastatin ameliorated diastolic dysfunction, left ventricular hypertrophy, and cardiac remodeling.
- Statin treatment did not alter angiotensin II-induced hypertension or hypercholesterolemia.
- Cardioprotection correlated with downregulated inflammatory markers (TGF-β, IL-6, TNF-α) and matrix remodeling factors (Collagen I, MMPs), and upregulated eNOS.
Conclusions:
- Pravastatin's benefits in DHF are likely due to cholesterol-independent, pleiotropic effects.
- These effects involve improved endothelial function and reduced vascular inflammation, potentially via ROCK1.
- Pravastatin may be a beneficial treatment for patients with diastolic heart failure.
Background:
A substantial proportion of patients with heart failure have a normal ejection fraction and diastolic dysfunction. However, there are few data available to guide the therapy of these patients. The effects of statins on cardiac remodeling are well documented in animal models and it is reported that statin therapy revealed a survival benefit in patients with diastolic heart failure (DHF). However, the exact mechanisms of statins possibly explaining the decreased cardiovascular morbidity and mortality in patients with DHF have not been elucidated.
Methods:
We used 8-week-old male C57BL/6J mice, in which angiotensin II was subcutaneously infused for 4 weeks to mimic cardiac remodeling and fibrosis. They were treated with either normal saline or pravastatin in daily doses, which did not lower the serum cholesterol levels and blood pressure.
Results:
Pravastatin improved diastolic dysfunction in angiotensin II-induced hypertensive mice, which was associated with the amelioration of left ventricular hypertrophy and remodeling. However, statin treatment showed no effect on the increased systolic blood pressure or cholesterol levels by angiotensin II infusion. The cardioprotective effects of pravastatin were closely associated with the downregulation of collagen I, transforming growth factor-beta, matrix metalloproteinases-2 and -3, atrial natriuretic factor, interleukin-6, tumor necrosis factor-alpha, ROCK1 gene expression, and the upregulation of endothelial nitric oxide synthase gene expression.
Conclusions:
The beneficial effects of pravastatin on DHF and structural remodeling are through cholesterol- independent mechanism of statins or "pleiotropic" effects of statins involving improving or restoring endothelial function and decreasing vascular inflammation. These findings suggest the potential involvement of ROCK1. Thus, treatment with pravastatin might be beneficial in patients with DHF.
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