The Role Of PLK1in The Development Of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a pathophysiological syndrome characterized by elevated pulmonary vascular resistance and pulmonary arterial pressure, with features of vasoconstriction, vascular remodeling, thrombosis, pulmonary vascular endothelial cells, and smooth muscle cell proliferation, which lead to pulmonary vascular remodeling and consistant increasing of pulmonary vascular resistance, and eventually result in congestive right heart failure, or all heart failure.The cause of pulmonary hypertension is complicated, so far, its pathogenesis is not yet entirely clear. Previous studies have shown that the development of PAH can not be interpreted with a single process, as it involves cells, humoral factors and molecular genetics and other aspects. Further investigations into the pathogenesis of pulmonary hypertension are of great significance in slowing or even reversing the process of pulmonary hypertension to improve the prognosis and the quality of life of patients with pulmonary hypertension.Serine threonine protein kinase Polo-like kinase1(Plkl) is one of the key factors to regulate cell division and proliferation in DNA replication, which play inmprotant role in centrosome maturation, spindle formation, chromosome segregation and cytokinesis mitosis. Reduction of PLK1arests cell cycle arrest, inhibits of cell proliferation and induces apoptosis. Excessive proliferation and reduced apoptosis of pulmonary artery smooth muscle cells and endothelial cells play a crucial role in the development and progression of pulmonary hypertension, but no preliminary research about Plkl in pulmonary hypertension development has been reported.This study investigated the effects and mechanisms of PLK1in the development of pulmonary hypertension.This study built hypoxia-induced pulmonary hypertension in mice model, and found Plkl expression levels increased in the lungs of mice and was positve correlated with pulmonary artery pressure. Heterozygous Plkl-deficient mice was not easy to form pulmonary high pressure compared with wild-type mice; Plkl inhibitor BI2536could block and reverse the development of hypoxia-induced pulmonary hypertension in mice.To further investigate PLK1activation role in the development of pulmonary hypertension, we used confocal PLKl positioning, found that the PLK1located in the pulmonary artery smooth muscle cells; PLK1regulation of pulmonary hypertension development was found not denpendent on the systolic and diastolic function of the pulmonary vascular via the using of pulmonary artery strip; at the cellular level, we further confirmed that Plkl expression levels increased in hypoxia inducible artery smooth muscle cells and positively correlated with time course of hypoxia duration. Inhibition of PLKl of human arterial smooth muscle cells decreased proliferation ability, and under hypoxic conditions, HIF-alpha expression was positively correlated with Plkl expression levels, providing a hypothesis that HIF-alpha regulate Plkl expression to elucidate the molecular mechanisms PLK1development of pulmonary hypertension. We also used systemic-pulmonary shunt model in rats to imitate pulmonary hypertension of congenital heart disease, to further disscuss the correlation of PLK1expression with pulmonary shunt pulmonary hypertension, and the practicality of prevention and treatment of systemic-pulmonary shunt hypertension through PLK1inhibitor. In summary, our study showed that hypoxia increase plkl expression via upregulating HIF-alpha to promote the development of pulmonary hypertension. Blocking the function of PLK1may reduce, delay or even reverse the development of pulmonary hypertension, provide new therapeutic targets to pulmonary arterial hypertension.