Calcium-calmodulin mediates bradykinin-induced MAPK phosphorylation and c-fos induction in vascular cells

The vasoactive peptide bradykinin (BK) has been implicated in the pathophys iology of a number of vascular wall abnormalities, but the cellular mechani sms by which BK generates second messengers that alter vascular function ar e as yet undefined. Exposure of vascular smooth muscle cells (VSMC) to BK ( 10(-7) M) produced a rapid and transient rise in intracellular calcium, whi ch preceded an increase in tyrosine phosphorylation of mitogen-activated pr otein kinase (MAPK). MAPK activation by BK was observed as early as 1 min, peaked at 5 min, and returned to baseline by 20 min. Treatment of cells wit h the intracellular calcium chelator EGTA-acetoxymethyl ester inhibited BK- stimulated MAPK activation, suggesting that intracellular calcium mobilizat ion contributes to the activation of MAPK. The calmodulin inhibitor W-7 als o markedly inhibited BK-induced MAPK phosphorylation in the cytoplasm as we ll as in the nucleus. Moreover, the BK-induced increase in c-fos mRNA level s was significantly inhibited by the calmodulin inhibitor, indicating that calmodulin is required for BK signaling leading to c-fos induction. These r esults implicate the calcium-calmodulin pathway in the mechanisms for regul ating MAPK activity and the resultant c-fos expression induced by BK in VSM C.