Mechanisms involved in improving cardiac fibrosis in SHR by pravastatin

M Kassan, MJ Montero, A Rodríguez-Barbero, S Velasco, MA Sevilla. Universidad de Salamanca, Fisiología y Farmacología, Spain

Cardiac hypertrophy accompanied by fibrosis is a major cause of heart failure related deaths. Our group reported that pravastatin prevent early left ventricular hypertrophy in spontaneously hypertensive rats (SHR). The aim of this study was to investigate the mechanisms involved in the ability of pravastatin to prevent cardiac remodeling caused by hypertension. SHR and their corresponding normotensive controls Wistar-Kyoto (WKY) rats were treated with pravastatin (20 mg kg-1 per day, administered in drinking water for 4 weeks). Systolic blood pressure (SBP) was monitored using the tail cuff method. At the end of the study heart was removed, left ventricular weight/body weight ratio was used as left ventricular hypertrophy index (LVH). Left ventricle slices stained with sirius red were analyzed to determine fibrosis and cardiomyocytes area. Fibrosis marker proteins such as collagen-I, fibronectin and PAI-1 were also quantified in tissue homogenates using western blotting. Pravastatin treatment attenuated the development of hypertension in SHR group compared to untreated group (159±2 vs 173±1 mmHg, p<0.001); no differences between WKY treated (140±1 mmHg) and untreated groups (141±1 mmHg) were observed. Hypertensive rats shown LVH compared to normotensive rats. Pravastatin significantly reduced this parameter only in SHR (from 2.77±0.01 to 2.57±0.02, p<0.001) and this effect was accompanied by decrease in cardiomyocyte size. Interstitial fibrosis was dramatically reduced by pravastatin treatment in SHR, there was also a decrease in collagen-I and fibronectin expression. Elevated levels of PAI-1 are associated with greater risk of cardiovascular disease and it has shown to be critical in fibrosis associated with animal hypertension models. Pravastatin reduced expression of PAI-1 in SHR to values close to those of normotensive rats, whereas treatment did not produced changes in WKY. In conclusion, pravastatin prevents cardiac hypertrophy resulting from hypertension by decreasing the cardiomyocyte size and fibrosis. The effect of pravastatin on PAI-1 expression contributes to these beneficial effects.