A Novel Pleiotropic Effect of Statins: Enhanced Cardiomyocyte β2-Adrenoceptor Responsiveness

Abstract

Pleiotropic effects of statins on endothelial cells, vascular smooth muscle cells and fibroblasts are well-established and contribute to reduced cardiovascular morbidity and mortality. Here we test whether these effects extend to the cardiomyocyte. Adult rat ventricular cells were maintained in culture +/- 10 μM simvastatin (SIMV). After 48h, shortening and [Ca2+]i responses to β1-adrenoceptor stimulation were identical in SIMV and control cells, but a marked SIMV potentiation of the β2 response was seen (Figure 1). Statins mediate their effects through cholesterol-dependent and -independent pathways. Caveolae are cholesterol-dependent signalosomes that limit the magnitude of β2, but not β1, responses in the adult cardiomyocyte. Therefore we surmised that SIMV's effects could be mediated through caveolar disruption. Indeed, the mean density of caveolae (visualised by electron microscopy) was reduced in SIMV-treated cells (0.63 ± 0.08 vs. 0.86 ± 0.11 μm−1; P<0.05; n=9 cells from 3 hearts). This is the first demonstration of effects of statins on the β responsiveness of the adult cardiomyocyte. These data suggest a novel mechanism for the beneficial effects of statins in heart failure - enhancing the contractile reserve of the failing heart, through effects on the caveolar signalosome.View Large Image | View Hi-Res Image | Download PowerPoint Slide