C838A Polymorphism of P27kip1 Gene

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The balance between cell proliferation and cell quiescence is regulated by a variety of cellular mediators, in which cyclin-dependent kinases and their inhibitors play a very important role. The CDK inhibitor p27 is very important in inhibition of pulmonary artery smooth cell growth, both in vitro and in vivo. In chronically hypoxic mice lungs, hypoxia significantly inhibited p27 expression, showing a 98% decrease in p27 [72]. The inhibition of hypoxic pulmonary vascular remodelling by heparin required the p27 expression [73]. In p27 null mice exposed to hypoxia, heparin did not inhibit cell proliferation in pulmonary vessels. These data strengthen the previous findings that p27 is the only CDK inhibitor involved in hypoxia-induced pulmonary hypertension [73].

Gene encoding p27 is localized on chromosome 12p 13. The known C838A polymorphism of p27 gene is associated with decreased activity of promoter region (32). The A838 allele is associated with decreased expression of p27 and cardiovascular diseases. We have demonstrated that genotype A838A was apparently twice as prevalent in highlanders with HAPH than the controls (%2 = 6.407, p = 0.04). The frequency of the A838 allele was significantly higher in the HAPH group (%2 = 5.520, p = 0.01, see table 6). These genetic data from human studies strongly support the previous observations made in mice that p27 is the only CDK inhibitor involved in hypoxic pulmonary hypertension.

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