Prevention of hypoxic pulmonary hypertension by hypoxia-inducible expression of p27 in pulmonary artery smooth muscle cells.

Abstract

Hypoxia-induced proliferation of pulmonary artery smooth muscle cells (SMCs) is important in the development of hypoxic pulmonary hypertension (HPH). We constructed a lentivirial vector containing a smooth muscle-specific promoter and six copies of hypoxia response element to co-drive the expression of p27, the key cyclin-dependent kinase inhibitor that blocks the G1 to S phase transition in cell cycle progression, in pulmonary artery SMCs in hypoxia. Then in vivo we examined the prevention effects of the vector on HPH in mice and in vitro the specificity on the hypoxia-inducible expression of p27 in pulmonary artery SMCs. Hypobaric hypoxia for 4 weeks resulted in significant increases in the right ventricular systolic pressure, the ratio of right ventricle to left ventricle plus septal weight and the muscularization of pulmonary vessels in mice. Administration of the vector before hypoxia significantly prevented the effects of hypoxia. In vitro, the vector exhibited hypoxic inducibility and relatively specific expression in pulmonary artery SMCs, inhibited the hypoxia-induced proliferation of pulmonary artery SMCs and arrested more cells at G0/G1 phase. These results demonstrate that the hypoxia-inducible p27 expression prevents the development of HPH in mice.