Statins suppress MMP2 secretion via inactivation of RhoA/ROCK pathway in pulmonary vascular smooth muscles cells

Recent studies have shown that statins ameliorate hypoxia-induced pulmonary hypertension in animal models. Yet, the underlying molecular mechanisms have not been completely understood. Here, we investigated the hypothesis that statins regulate vascular remodeling by modulation of matrix metalloproteinases (MMP) secretion in primary cultured pulmonary artery smooth muscle cells (PASMCs). Angiotensin II induced a concentration-dependent MMP2 secretion. A 2.75 fold increase was achieved by 100 nM angiotensin II stimulation for 24 h in primary cultured PASMCs (P < 0.01 versus control), which was reversed by silencing Ras homolog gene family member A (RhoA) or inhibition of its downstream Rho-associated kinase (ROCK). There was no effect of angiotensin II on the expression of tissue inhibitors of matrix metalloproteinases (TIMPs). Pre-exposure of cells to simvastatin concentration-dependently blocked angiotensin II-stimulated MMP2 release. MMP2 release was reduced to1.34 fold increase in the presence of 10 mu M simvastatin (P < 0.01 versus angiotensin II-stimulated cells). We further revealed that simvastatin suppression of RhoA activation mediated its inhibitory effect on angiotensin II-triggered MMP2 release. Similarly, simvastatin suppressed endothelin-1-induced MMP2 release through RhoA/ROCK pathway. These results indicated a novel statins-regulation of RhoA/ROCK signaling against pulmonary vascular remodeling, and suggest that statins could prove useful in targeting this pathway in pulmonary hypertension and other disease conditions. (C) 2008 Elsevier B.V. All rights reserved.