Amelioration Of Monocrotaline-induced Pulmonary Hypertension In Mice By Rosuvastatin

Background“Pulmonary arterial hypertension”(PAH) refers to pulmonary vascular disease affecting the arterioles that results in an elevation in pressure and vascular resistance, and which can decreases quality of life and shortens life expectancy significantly. PAH has the features of increased pulmonary arterial pressure and pulmonary resistance that are characterized by severe arteriopathy(including intimal hyperplasia as well as “muscularization” of the distal alveolar duct and pulmonary arteries, plexiform lesions and neointima) and which obstruct the pulmonary arteries and arterioles, eventually leading to chronic progressive disease of the pulmonary circulation.The precise cause of PAH is not known. Recent advances in basic scientific research point to abnormalities in the function of pulmonary endothelial cells as causing or contributing to the development of PAH. The essence of vascular endothelial dysfunction is the imbalance between damage and repair to endothelial cells.Endothelial progenitor cells(EPCs) are bone marrow-derived stem cells that can differentiate into mature endothelial cells. Studies have shown that EPCs play an important part in replacement of a dysfunctional endothelium and improvement of endothelial function. However, accumulated evidence suggests that the level of circulating EPCs is lower and the EPCs function is reduced in PAH.Intriguingly, several studies have demonstrated the potential modulatory role of statins on circulating EPCs and endothelial nitric oxide synthase(eNOS). Statins can mobilize EPCs in bone marrow and enhance their ability to proliferate and migrate to repair injured endothelial cells. Statins also can upregulate the expression and activation of eNOS(a key enzyme involved in the regulation of vascular function) by generating endothelium-derived relaxing factor. In the present study, circulating EPC and the modulatory role of statins on eNOS were investigated. ObjectivesTo evaluate the effect of rosuvastatin on the number of circulating endothelial progenitor cells(EPCs) and endothelial expression of eNOS in monocrotalineinduced pulmonary hypertension(PAH) rats. MethodsSixty Sprague–Dawley(SD) rats was divided into three groups of 20: control(group A), PAH + rosuvastatin group(group B), and PAH(group C). Monocrotaline(MCT; 60mg/kg) was injected(i.p.) to induce PAH. Rats in group B received rosuvastatin(10mg/(kg.day)) for 6 weeks. Peripheral blood(5mL) was aspirated from the femoral artery of each rat before and after 6 weeks of treatment. Mononuclear cells were isolated and subcultured to obtain EPCs. Small and moderately sized pulmonary arteries were collected 6 weeks later for histologic analyses. eNOS expression in endothelial cells of pulmonary arteries were then determined respectively at mRNA and protein levels. ResultseNOS expression at mRNA and protein levels and the number of circulating EPCs was reduced significantly in groups B and C compared with group A(P<0.05), and a significant difference between group B and group C(P<0.05) was observed. Vascular remodeling in small and moderately sized pulmonary arteries was attenuated markedly in group B compared with group C. ConclusionsThese results suggest that rosuvastatin can ameliorate the remodeling of pulmonary arteries in MCT-induced PAH rats by increasing the number of circulating EPCs and eNOS overexpression.