Ras/Rac-Dependent Activation of p38 Mitogen-Activated Protein Kinases in Smooth Muscle Cells Stimulated by Cyclic Strain Stress

Abstract

p38, a subfamily of the mitogen-activated protein kinases (MAPKs), is a crucial signal transducer between a variety of extracellular stimuli and gene expression in mammalian cells. This kinase is activated in cultured cells stimulated by heat shock, osmotic stress, and proinflammatory cytokines, but a similar activation of p38 MAPKs in vascular smooth muscle cells (SMCs) stimulated by mechanical stress has yet to be studied. We studied signal pathways leading to time- and strength-dependent p38 activation in rat SMCs in response to cyclic strain stress. p38 phosphorylation in stressed SMCs showed maximal activation at 10 minutes. This activation was significantly inhibited by pretreatment of the SMCs with pertussis toxin, a G-protein antagonist, and enhanced by treatment with suramin, a growth factor receptor antagonist, but opposite effects in the activation of extracellular signal-regulated kinases stimulated by mechanical forces were found. p38 activation was markedly reduced in stressed SMCs after protein kinase C depletion. Interestingly, SMC lines stably expressing dominant-negative ras (ras N17) or rac1 (rac1 N17) almost abolished p38 phosphorylation induced by cyclic strain stress. When p38 activation was inhibited by the specific inhibitor SB 202190, SMC migration, determined in a Boyden chamber in response to stimulation with platelet-derived growth factor-BB, and SMC proliferation, stimulated by cyclic strain stress, were abrogated. Thus, we provide the first evidence that cyclic strain stress rapidly activates p38 MAPKs via activation of protein kinase C ras/rac signal pathways, suggesting that p38 MAPKs are important signal transducers mediating the mechanical stress-induced cell responses essential for SMC migration and proliferation.

Mechanical Stretch-Induced Apoptosis in Smooth Muscle Cells Is Mediated by β 1 -Integrin Signaling Pathways

“…The p38 MAPK assay was performed as described previously. 29 The specificity of the band was confirmed by use of myelin basic protein as a substrate.…”

Cyclic tensile strain triggers a sequence of autocrine and paracrine signaling to regulate angiogenic sprouting in human vascular cells

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

“…The p38 pathway in vascular smooth muscle has been shown to be activated by reactive oxygen species (Kyaw et al, 2001;Yoshizumi et al, 2000), mechanical strain (Li et al, 1999;Li et al, 2000), hypoxia (Lin et al, 2000), and cytokines (Jung et al, 2001). Recent studies have also shown that arterial contraction induced by agonists such as endothelin-1, angiotensin II and Asterisks denote significant differences compared with the control treated with a vehicle (*, P<0.05).…”