Simvastatin protects against the development of monocrotaline-induced pulmonary hypertension in rats via a heme oxygenase-1-dependent pathway

Heme oxygease-1 (HO-1) is the rate-limiting enzyme in heme catabolism. Induction of HO-1 has been shown to have vasodilatory, anti-inflammatory, and proapoptotic effects. More recently, experimental studies suggested the potential of simvastatin as a novel therapy for pulmonary hypertension (PH); however, the underlying mechanism remains to be investigated. The aim of this study was to evaluate whether HO-1 is required for the pulmonary vascular protective effects of simvastatin. Simvastatin (2 mg/kg/day) was administered once daily to rats for 4 weeks after monocrotaline (MCT) injection. Zn-protoporphyrin (Znpp), a potent inhibitor of HO, was used to confirm the role of HO-1. The hemodynamic changes, right heart hypertrophy, interleukin-6 (IL-6) level, and HO-1 protein expression in lungs were measured at day 28. Simvastatin significantly ameliorated mean pulmonary arterial hypertension (20.6 mm Hg). In addition, perivascular infiltration of inflammatory cells and the level of IL-6 were decreased in simvastatin treatment group. Simvastatin also increased significantly lung HO-1 protein expression. Inhibiting HO-1 using Znpp resulted in a loss of the effect of simvastatin in MCT rats. These results suggest that HO-1 expression is critical for the vascular protective effects of simvastatin in MCT-induced PH rats.