Abstract 16128: Activation of Lung p53 by Non-Receptor Tyrosine Kinase Pyk2 Inhibition Suppresses Pulmonary Arterial Hypertension(PAH)
Background: PAH is an idiopathic refractory diseases characterized by uncontrolled vascular remodeling and increasing pulmonary arterial pressure. The therapies have been focused on regulating vasoconstriction, but their therapeutic effect has been limited. Although rapamycin, an immunosuppressant and imatinib, a receptor tyrosine kinase inhibitor were reported as a new therapeutic agents, safety concerns are unresolved issue. Regarding the roles of cellular signal transduction in vascular remodeling, we recently reported that non-receptor tyrosine kinase Pyk2 was activated by cardiovascular stresses, leading to promotion of inflammatory cell migration, proliferation, vascular remodeling. Based on the experimented study, here we report a novel role of Pyk2 and p53 in the pathogenesis of PAH.
Method: Pyk2-deficient (Pyk2-KO) mice were exposed to 10% hypoxia for 36 days to induce PAH.
Result: Lung Pyk2 was activated under hypoxia. In WT mice, the right ventricle systolic pressure (RVSP) increased from 24 to 54 mmHg (p<0.005 vs. baseline, n=10) because of pulmonary arteriolar stenosis caused by the proliferation of pulmonary arterial smooth muscles (PASMCs). In contrast, in Pyk2-KO mice, the increase of RVSP and arteriolar stenosis were inhibited. Furthermore, the proliferation of PASMCs was less, and apoptosis was facilitated. Pyk2 localized in the nucleus to facilitate interaction between p53 and MDM2 as a scaffold, leading to p53 degradation. We found that hypoxia changes the interaction between p53 and Pyk2. And p21 expression was increased in the lung of the Pyk2-KO mice. The expression of the HIF-1-alpha- inducible growth factor and chemokine was markedly attenuated in the lung of Pyk2-KO mice subjected to hypoxic stress. Nuclear translocation of hypoxia-inducible factor-1 (HIF-1)-alpha was also diminished in the lungs of Pyk2-KO mice.
Conclusion: Pyk2 affects multiple signals thereby promoting hypoxia-induced pulmonary stenosis and hypertension by facilitating migration and proliferation of PASMCs. Pyk2- KO mice are phenotypically normal at birth with a normal life span. Therefore Pyk2 could be a possible therapeutic target for PAH.
- © 2013 by American Heart Association, Inc.