Statins inhibit pulmonary artery smooth muscle cell proliferation by upregulation of HO-1 and p21^WAF1

Simvastatin is a 3-hydroxy-3-methylglutaryl- CoA reductase inhibitor, which has been shown to ameliorate the development of pulmonary hypertension in animal model by suppression of pulmonary artery smooth muscle cells (PASMCs) proliferation, yet its underlying molecular mechanisms are not completely understood. In this study, we show that simvastatin dose-dependently inhibited serotonin-stimulated PASMCs proliferation. This was accompanied with the parallel induction of heme oxyganase-1 (HO-1) and upregulation of p21 ^WAF1. More importantly, we found that Tin-protoporphyrin (SnPP), a selective inhibitor of HO-1, could block the effect of simvastatin on inhibition of cell proliferation in response to serotonin and abolish simvastatin-induced p21^WAF1 expression. The inhibitive effect of simvastatin on cell proliferation was also significantly suppressed by silencing p21^WAF1 with siRNA transfection. The extent of effect of SnPP on inhibition of cell proliferation was similar to that of lack of p21^WAF1 by siRNA transfection. Taken together, our study suggests that simvastatin inhibits PASMCs proliferation by sequential upregulation of HO-1 and p21^WAF1 to benefit pulmonary hypertension.