Evidence for modulation of smooth muscle force by the p38 MAP kinase/HSP27 pathway

Abstract

Mitogen-activated protein (MAP) kinases signal to proteins that could modify smooth muscle contraction. Caldesmon is a substrate for extracellular signal-related kinases (ERK) and p38 MAP kinases in vitro and has been suggested to modulate actin-myosin interaction and contraction. Heat shock protein 27 (HSP27) is downstream of p38 MAP kinases presumably participating in the sustained phase of muscle contraction. We tested the role of caldesmon and HSP27 phosphorylation in the contractile response of vascular smooth muscle 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 response remained unaffected. SB-203580 reduced muscle contraction and inhibited p38 MAP kinase and HSP27 phosphorylation but had no effect on ERK MAP kinase and caldesmon phosphorylation. In permeabilized muscle fibers, SB-203580 and a polyclonal anti-HSP27 antibody attenuated ET-1-dependent contraction, whereas PD-098059 had no effect. These results suggest that ERK MAP kinases phosphorylate caldesmon in vivo but that activation of this pathway is unnecessary for force development. The generation of maximal force may be modulated by the p38 MAP kinase/HSP27 pathway.

Difference in Signal Transduction Mechanisms Involved in 5-Hydroxytryptamine- and U46619-Induced Vasoconstrictions.

“…noradrenaline were attenuated by p38 inhibition (Yamboliev et al, 2000;Ohanian et al, 2001;Meloche et al, 2000). However, there have been only a few reports of p38 inhibition on the vasoconstriction induced by both 5-HT and TXA2.…”

“…But there has been considerable evidence more recently to indicate that vasoconstrictive agonists activate multiple ancillary pathways that modulate the contractile response: protein kinase C (PKC) (Horowitz et al, 1996), Rho family G proteins (Somlyo and Somlyo, 2000), nonreceptor tyrosine kinases (Hughes and Wijetunge, 1998), and extracellular signal-regulated kinases (ERK1/2) (Ishihata et al, 2002) have been shown to play roles in smooth muscle contraction. Moreover, stress-activated protein kinases have also been implicated in sustained contraction through regulation of the phosphorylation of p38 mitogenactivated protein kinase (p38 MAPK) (Yamboliev et al, 2000). Activation of phospholipase C, Ca 2+ channels, tyrosine kinase and ERK MAPK have also been reported to be involved in 5-HTinduced contraction (Watts, 1998).…”

Regulation of contractility by Hsp27 and Hic-5 in rat mesenteric small arteries

“…In many smooth muscles, p38 MAPK activation is linked to contraction (10,29,34,36,56), and in vascular tissues and gastrointestinal smooth muscle cells, Hsp27 phosphorylation is important for sustained contraction (32,40). Although in rat aorta smooth muscle cells, the inhibition of p38 MAPK and Hsp27 showed a significant reduction in contraction to ANG II but not NE (34).…”

Beyond the dogma: novel β2-adrenoceptor signalling in the airways

“…More recent studies have suggested that mitogen-activated protein (MAP) kinases may also impact on contractile responses in airways [64,[77][78][79] and other types of smooth muscle [80,81]. In particular, MLC20 are the proposed substrate of extracellular signal-regulated kinase (ERK)1 and 2 [82][83][84].…”