Pyk2/Cakβ Negatively Regulates Angiotensin Ii-Induced Vascular Hypertrophy
PYK2/CAKβis a Ca2+-dependent tyrosine kinase which has been shown to activate Src tyrosine kinase and downstream mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38 MAPK depending on a cell-type. Although angiotensin II (Ang II)-induced activation of PYK2 has been implicated in vascular remodeling, the precise role of PYK2/CAKβin Ang II-induced MAPK family activation and cell growth in vascular smooth muscle cells (VSMCs) remain largely unclear. To resolve this question, cultured rat aortic VSMCs were transfected with adenoviral vector expressing either wild type rat PYK2/CAKβ(PykWT) or its dominant-negative K457A mutant (PykDN), and MAPK family activation and protein synthesis were compared. The activation of MAPKs was measured by immunoblotting with the phospho-specific antibodies that selectively recognize the activated MAPKs. Protein synthesis was determined by 3H-leucine incorporation. Both PykWT and PykDN transfection had no effect on Ang II-induced ERK activation. By contrast, PykWT transfection inhibited Ang II-induced JNK and p38 MAPK activation, whereas PykDN transfection markedly enhanced their activation. Interestingly, Ang II-induced 3H-leucine uptake was totally blocked by PykWT transfection. However, PykDN transfection had no effect on Ang II-induced3H-Leucine uptake. From these data, we conclude that PYK2/CAKβnegatively regulates Ang II-induced vascular hypertrophy possibly through its inhibitory effect on JNK and p38 MAPK, providing new insight into the signal transduction mechanism of vascular remodeling.