Rat Pulmonary Artery Smooth Muscle Cells

Background The excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), which result in pulmonary vascular remodeling, are crucial patholo... More

Background The excessive proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), which result in pulmonary vascular remodeling, are crucial pathological features of pulmonary arterial hypertension (PAH). Protein S-nitrosylation (SNO), which is a modification by which a nitric oxide (NO) group is added to a cysteine residue, has been shown to play a critical role in PASMC proliferation and PAH, but the underlying mechanism remains largely unknown. Methods Using a combination of membrane and nuclear localization analyses, iodoTMT switch assays, molecular biology techniques, and in vitro and in vivo approaches, we investigated the effects of ANXA2 SNO at cysteine 133 (Cys133) on PASMC proliferation and migration in PAH. Results ANXA2 protein expression was increased in PASMCs from rats with PAH. ANXA2 knockdown significantly inhibited excessive PASMC proliferation and migration. Additionally, inhibiting ANXA2 or conditionally knocking down ANXA2 in PASMCs ameliorated pulmonary vascular remodeling in experimental models of PAH. Moreover, we found that the NO donor S-nitrosoglutathione (GSNO) mediated the SNO of ANXA2 at Cys133 under hypoxic conditions. S-nitrosylated Cys133 (SNO-Cys133) of ANXA2 inhibited hypoxia-mediated PASMC proliferation and migration by regulating the subcellular localization of ANXA2 in cells. In addition, SNO-Cys133 of ANXA2 regulated the WNT pathway by inhibiting ANXA2 phosphorylation at Tyr24. Finally, SNO-Cys133 of ANXA2 ameliorated pulmonary vascular remodeling and improved RV function in vivo. Conclusions SNO-Cys133 of ANXA2 suppressed ANXA2 relocation and the WNT pathway to ameliorate pulmonary vascular remodeling in PAH. Less