Proline‐rich tyrosine kinase regulates NF‐κB and PPARγ to promote hypoxia‐induced proliferative phenotype of human pulmonary artery smooth muscle cells (1175.1)

Hypoxia stimulates pulmonary hypertension in part by increasing the proliferation of pulmonary vascular wall cells via sustained activation of MAP kinase ERK 1/2, NF‐κB, and downregulation of PPARγ levels. However, the upstream signaling events that mediate NF‐κB upregulation and PPARγ downregulation remain unknown. We examined the role of Proline‐rich tyrosine kinase 2 (Pyk2) in hypoxia‐induced proliferation of human pulmonary artery smooth muscle cells (HPASMC). Exposure of HPASMC to hypoxia (1% O2) for 72 hrs resulted in the activation of Pyk2. siRNA‐mediated Pyk2 depletion or its pharmacological inhibition attenuated hypoxia‐induced HPASMC proliferation. Pyk2 inhibition attenuated hypoxia‐induced: 1) ERK 1/2 activation, 2) NF‐κB transcriptional activity and 3) reductions in PPARγ mRNA levels. Conversely, siRNA‐mediated PPARγ depletion enhanced, whereas PPARγ overexpression attenuated HPASMC Pyk2 activation. Exposing C57BL/6 mice to 10% O2 for 3 weeks reduced lung PPARγ but increased Pyk2 levels compared to normoxic mice. Also, Pyk2 levels were higher in pulmonary vascular tissues of smooth muscle‐specific PPARγ knockout mice compared to control mice. Taken together, these findings point to a crucial role of Pyk2 in the mechanism that promotes hypoxia‐induced proliferative phenotype of HPASMC.Grant Funding Source: Supported by: grants from VA Research Service (1I01BX001910, CMH), NIH (HL102167, CMH), and AHA‐SDG