Molecular biological study of the role of Rho protein in hypoxic air induced pulmonary hypertension

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To assess the molecular biological role of Rho-kinase in hypoxic air induced pulmonary hypertension, we used human cultured pulmonary arterial smooth muscle cells(HPASMC) and examined the uptake of BrdU, progression of cell cycle, expression of CDK inhibitors, in the presence/absence of Rho-kinase inhibitor(Y-27632) under the normoxic state, hypoxic state and under the shear stresses.1) Hypoxia evoked proliferation of HPASMC, whereas Y-27632 significantly suppressed the effect of hypoxia2) Hypoxia suppressed the expression of protein of CDK inhibitor, p21 and p27, whereas Y-27632 attenuated hypoxia-induced suppression of p27 but not that of p21.3) Y-27632 did not affect the proliferation of HPASMC in which p27 was suppressed by transfected siRNA.4) Hypoxia and shear stress concomitantly augmented proliferation of HPASMC, whereas Y-27632 attenuated such an effect.5) Y-27632 attenuated hypoxia- and shear stress-induced suppression of mRNA of p27.These results suggest that Rho-kinase exerts its proliferative effect on HPASMC under the hypoxia and shear stress by suppressing p27, a CDK inhibitor.