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Published on: September 25, 2017
Effect of pravastatin on development of left ventricular hypertrophy in spontaneously hypertensive rats
Tsung-Ming Lee1, Mei-Shu Lin, Tsai-Fwu Chou
1Cardiology section, Dept. of Medicine, Taipei Medical Univ. and Hospital, 252 Wu-Hsing St., Taipei, Taiwan.
Insights
Pravastatin reduces cardiac hypertrophy in spontaneously hypertensive rats by decreasing endothelin-1 (ET-1) expression, independent of blood pressure changes. This effect is linked to mevalonate metabolism.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Molecular Biology
Background:
- Endothelin (ET)-1 is implicated in cardiac hypertrophy development.
- Spontaneously hypertensive rats (SHR) serve as a model for studying cardiac hypertrophy.
Purpose of the Study:
- To investigate pravastatin's effect on ventricular hypertrophy in SHR.
- To determine if pravastatin attenuates hypertrophy by reducing ET-1 expression.
Main Methods:
- SHR were treated with vehicle, bosentan, pravastatin, mevalonate, hydralazine, or pravastatin + mevalonate for 8 weeks.
- Left ventricular mass index and cardiomyocyte size were measured.
- Myocardial ET-1 levels and preproET-1 mRNA were assessed using real-time quantitative RT-PCR and immunohistochemistry.
Main Results:
- Pravastatin and bosentan significantly decreased left ventricular mass index and cardiomyocyte size.
- SHR exhibited significantly higher myocardial ET-1 levels and preproET-1 mRNA compared to controls.
- Pravastatin administration inhibited elevated tissue ET-1 levels; effects were reversed by mevalonate.
Conclusions:
- The cardiac endothelin system plays a crucial role in early ventricular hypertrophy in SHR.
- Pravastatin possesses cardiac antihypertrophic properties independent of hemodynamic and hypolipidemic effects.
- Pravastatin's antihypertrophic effects are linked to decreased cardiac ET-1 levels via mevalonate metabolism.
Abstract:
Endothelin (ET)-1 has been implicated in the development of cardiac hypertrophy. We investigated the effect of pravastatin on development of ventricular hypertrophy in spontaneously hypertensive rats (SHR) and whether the attenuated hypertrophic effect was via reduced ET-1 expression. Normolipidemic SHR were treated with one of the following therapies for 8 wk: vehicle, the nonselective ET receptor antagonists bosentan, pravastatin, mevalonate, hydralazine, or combination of pravastatin + mevalonate from the age of 8 wk at the very early stage of cardiac hypertrophy. Treatment with bosentan and pravastatin significantly decreased left ventricular mass index for body weight and cardiomyocyte sizes isolated by enzymatic dissociation. The myocardial ET-1 levels and preproET-1 mRNA assessed using real-time quantitative RT-PCR were significantly higher (both P < 0.001) in the SHR compared with Wistar-Kyoto rats. The increased tissue ET-1 levels can be inhibited after pravastatin administration. Immunohistochemical analysis confirmed the changes of ET-1. Left ventricular mass index for body weight correlated positively with tissue ET-1 levels (P = 0.0004). A dissociation between the effects of blood pressure and cardiac structure was noted, because pravastatin and hydralazine reduced arterial pressure similarly. Pravastatin-induced effects were reversed by the addition of mevalonate. In conclusion, these results suggest a crucial role of cardiac endothelin system in the early development of ventricular hypertrophy in the SHR. Pravastatin is endowed with cardiac antihypertropic properties that are independent of its hemodynamic and hypolipidemic effects and appear to be related to their capacity to decrease cardiac ET-1 levels, which is linked to mevalonate metabolism.
