The role of Ca(2+) sensitive tyrosine kinase PYK2 as a molecule to transmit cardiovascular stresses

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Atherosclerosis is an inflammatory process initiated by endothelial cell (EC) dysfunction in which intracellular reactive oxygen species (ROS) plays crucial role. The therapy to control atherosclerosis has not been fully developed. Redox sensitive tyrosine kinase, PYK2 has been shown to promote inflammation. We here show for the first time that ROS/p21-mediated premature senescence and p21-related synthesis of inflammatory molecules was induced in endothelium just at 7 days after high cholesterol diet and in PYK2 deficiency, these events and eventual atherosclerosis were markedly inhibited. Methods: PYK2 deficient mice (PYK2-KO) were crossbred with ApoE deficient mice (ApoE-KO) and PYK2/ApoE double deficient mice (PYK2/ApoE-D-KO) were established. Four-week-old mice were fed with high-cholesterol-diet for 8 weeks. Results: Atherosclerotic area in the thoracic aorta of PYK2/ApoE-D-KO decreased to 55% of ApoE-KO (p<0.01). Bone marrow replacement experiment revealed that PYK2 deficiency i … More n the vascular wall and in the hematopoietic cells similarly contributes to this reduction. Further analysis was performed at day 7 after diet. Syntheses of VCAM1, MCP-1, LOX-1 and ROS in the endothelium of the thoracic aorta of PYK2/ApoE-D-KO were 48%, 31%, 78% and 74% lower than ApoE-KO (each p<0.05) at 7 days after diet. PYK2 activated NADPH oxidase through upregulation of VAV2/Racl. Expression of p21 protein and senescence associated-□-gal-activity in endothelium of aorta increased in ApoE-KO-mice at day 7, whereas treatment with NADPH-inhibitor decreased p21 protein level and this increase in p21 protein level were abolished in ApoE/PYK2-D-KO mice. Treatment with p21-siRNA in cultured WT-ECs reduced expression of VCAM-1, MCP-1 and LOX-1. Expression of ROS-dependent transcription factor, Ets-1, markedly decreased in PYK2-KO-ECs and its knockdown abolished molecular induction in WT-ECs. Conclusion: PYK2 initiate atherosclerosis through ROS/p21-mediated endothelial premature senescence. Thus, PYK2 is a potential therapeutic target to control development of atherosclerosis. Less