Statins, inhibitors of
3-hydroxy-3-methylglutaryl-coenzyme A reductase, are widely prescribed for
hypercholesterolemia. With the increasing use of
statins, numerous reports demonstrated that
statins can cause damage to skeletal muscles. However, the toxicities of
statins on vascular smooth muscle, which are essential to cardiovascular homeostasis, have not been previously described. Here, we examined the effects of
simvastatin on the contractile function and the integrity of vascular smooth muscle in isolated rat thoracic aortic rings, primary cultured vascular smooth muscle cells (VSMCs) in vitro and rats in vivo. In aortic rings,
simvastatin suppressed the normal agonist-induced contractile responses in time- and concentration-dependent manners (0.86 g ± 0.11
at 10 μM
simvastatin for 24 h compared with 1.89 g ± 0.11 at control). The suppression persisted in the endothelium-denuded aortic rings and was irreversible even after wash-out of
simvastatin.
Simvastatin suppressed the contraction induced by
Bay K8644, an activator of voltage-operated Ca²⁺ channel (VOCC) in rat aortic rings and abolished agonist-induced intracellular Ca²⁺ increase in VSMCs. The
simvastatin-induced contractile dysfunction was reversed by the supplementation of
mevalonate and geranylgeranylpyrophosphate, precursors for protein isoprenylation. Consistently, activation of RhoA, a representative isoprenylated
protein, was disrupted by
simvastatin in VSMCs and RhoA-mediated phosphorylation of MYPT1 and CPI-17, and tonic tension were also suppressed. Notably, prolonged treatment of
simvastatin up to 48 h induced apoptosis of vascular smooth muscle in aortic rings. Most importantly,
simvastatin treatment in vivo significantly attenuated the agonist-induced vasoconstriction in rats ex vivo and induced a decrease in
luminal area of the vascular wall. Collectively, these results demonstrate that
simvastatin can impair the normal vascular contractility by disturbing Ca²⁺ influx and RhoA activity, ultimately leading to apoptosis and structural remodeling.