Reduction of Atherogenesis in the Knock-out Mice of Tyrosine Kinase PYK2 which plays Essential Role in Cell Migration and Cytokine Induction

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PYK2 is the tyrosine kinase that play critical role in cell migration and cytokine induction. Meanwhile, these cell functions is critical for atherogenesis. We therefore pursued the functional role of PYK2 in atherogenesis. We adopted ApoE deficient mice as model mice. We histologically compared atherosclerotic region of ApoE knockout mice with that of ApoE, PYK2 double knockout mice, which were fed with high fat diet. The area of atherosclerotic region in PYK2, ApoE double knockout mice was much smaller than that in ApoE deficient mice, which was caused by decrease in the number of infiltrating monocytes into atherosclerotic region. Also, induction of IL-1beta or TNFalpha as well as expression of VCAM on endothelial cells or production of PAI-1 in the atherosclerotic region of ApoE, PYK2 double knockout mice was much reduced than that of the ApoE knockout mice. Further, PYK2 on endothelial cells in the atherosclerotic region of ApoE deficient mice was strongly tyrosine-phosphorylated. Tyrosine phosphorylation of Src or the amount of total tyrosine phosphorylated protein were significantly increased in the atherosclerotic region of ApoE knockout mice, whereas their increase was dramatically abolished in the atherosclerotic region of ApoE, PYK2 double knockout mice. Moreover, expression of the cell cycle regulatory proteins, p16 or p21, on the endothelial cells of ApoE, PYK2 double knockout mice was significantly reduced in comparison to that of ApoE knockout mice. Taken together, the impaired cell migration and altered cytokine production of monocyte in PYK2 deficient mice leads to reduced severity of atherosclegenesis in PYK2, ApoE deficient mice in comparison to ApoE deficient mice. Thus, these experimnt revealed at the first time that PYK2 plays critical role in atherogenesis.