Inhibition of cGMP phosphodiesterase 5 suppresses matrix metalloproteinase-2 production in pulmonary artery smooth muscles cells
Abstract
1. It has been shown that the beneficial effects of phosphodiesterase (PDE) 5 inhibition on pulmonary hypertension (PH) are associated with the induction of vascular relaxation and suppression of the proliferation of pulmonary artery smooth muscle cells (PASMC). In the present study, we investigated whether PDE5 inhibition affects the production and/or secretion of matrix metalloproteinases (MMPs) in PASMC, resulting in extracellular matrix remodelling in the pulmonary vasculature and, thus, the development of PH. 2. Primary cultured PASMC were stimulated with endothelin (ET)-1 and MMP-2 production and RhoA activation were then determinded using gelatin zymography and a GTP-bound RhoA assay, respectively. The effects of the selective PDE5 inhibitor sildenafil and subsequent protein kinase G-specific inhibitor Rp-8Br-cGMPs on MMP-2 production and RhoA activation were further exmamined. 3. Endothelin-1 (1-1000 nmol/L) concentration-dependently stimulated MMP-2 production and/or secretion in primary cultured PASMC, with 100 nmol/L ET-1 causing a 2.41-fold increase in MMP-2 production compared with control (P < 0.01). This increase in MMP-2 production was accompanied by RhoA activation, which was abolished by preincubation of cells with 10 micromol/L Y27632, an inhibitor of Rho-associated kinase (ROCK). Furthermore, 10 micromol/L Y27632 abolished the ET-1-induced production of MMP-2. 4. The selective PDE5 inhibitor sildenafil (0.1-1 micromol/L) concentration-dependently reduced…
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