Simvastatin Improved Pulmonary Arterial Hypertension In Rats By Regulating Small G Proteins

Background The etiology and pathophysiology of pulmonary arterial hypertension are not fully understood. Recent researches have proved that the statins could improve pulmonary arterial hypertension. But the mechanisms of statins in pulmonary arterial hypertension are not fully clear. Small G proteins are important pharmacological targets of statins. The research aimed to whether simvastatin improved pulmonary arterial hypertension by regulating small G proteins.Methods We constructed the rat model of pulmonary arterial hypertension by intraperitoneal injection of monocrotaline, and gave simvastation to therapy. We determined the small G protein family members’expression by immunohistochemistry and Western blot, the mRNA level of small G proteins by PCR, and determined the apoptosis and proliferation of vascular endothelial cells.The cellular model of pulmonary arterial hypertension was constructed with human pulmonary arterial endothelial cells treated with monocrotaline pyrrole. And we separately treated with simvastatin, mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Then we observed the apoptosis and proliferation of vascular endothelial cells, determined the proteins and mRNA levels of small G proteins by Western blot and PCR.Results Animal experiment showed that the pulmonary arterial hypertension rats had increased mean pulmonary arterial pressure, obvious vascular remodeling, and increased protein and mRNA levels of caspase-3, proliferating cell nuclear antigen and small G proteins family members. Administration of simvastatin could improve these changes.In vitro, the monocrotaline pyrrole group had an obvious proliferation of vascular endothelial cells, and increased protein and mRNA levels of caspase-3, proliferating cell nuclear antigen and small G proteins family members. Administration of simvastatin could improve these changes. After treated with mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate, we observed increased mRNA levels of RhoA, ROCK1, Rab1and Rac1, and increased protein levels of RhoA and Rab1.Conclusions Simvastatin could improve the apoptosis and proliferation of vascular endothelial cells, vascular remodeling and the development of pulmonary arterial hypertension. Inhibition of RhoA/ROCK1, Rab1and Rac1played great roles in these effects of simvastatin. Simvastatin decreased the RhoA/ROCKloverexpression, the protein synthesis of Rabl by inhibition of mevalonate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate.