Evidence for modulation of smooth muscle force by the p38 MAP kinase/HSP27pathway

Mitogen-activated protein (MAP) kinases signal to proteins that could modif y smooth muscle contraction. Caldesmon is a substrate for extracellular sig nal-related kinases (ERK) and p38 MAP kinases in vitro and has been suggest ed to modulate actin-myosin interaction and contraction. Heat shock protein 27 (HSP27) is downstream of p38 MAP kinases presumably participating in th e sustained phase of muscle contraction. We tested the role of caldesmon an d HSP27 phosphorylation in the contractile response of vascular smooth musc le by using inhibitors of both MAP kinase pathways. In intact smooth muscle , PD-098059 abolished endothelin-1 (ET-1)-stimulated phosphorylation of ERK MAP kinases and caldesmon, but p38 MAP kinase activation and contractile r esponse remained unaffected. SB-203580 reduced muscle contraction and inhib ited p38 MAP kinase and HSP27 phosphorylation but had no effect on ERK MAP kinase and caldesmon phosphorylation. In permeabilized muscle fibers, SB-20 3580 and a polyclonal anti-HSP27 antibody attenuated ET-1-dependent contrac tion, whereas PD-098059 had no effect. These results suggest that ERK MAP k inases phosphorylate caldesmon in vivo but that activation of this pathway is unnecessary for force development. The generation of maximal force may b e modulated by the p38 MAP kinase/HSP27 pathway.