The function of Mnk1 in vascular smooth muscle cells

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Angiotensin II(AngII) treatment resulted in increased Mnk1 activity and eIF4E phosphorylation in rat vascular smooth muscle cells(VSMC). Expression of a dominant-negative Mnk1 mutant abolished AngII-induced eIF4E phosphorylation. ERK, but not p38MAP kinase, was required for angII-induced Mnk1-eIF4E activation. Further, dominant-negative constructs for Ras, but not for Rho or Rac, abolished angII-induced Mnk1 activation. Treatment of VSMC with a specific inhibitor of Mnk1 resulted in dose-dependent decreases in angII-stimulated protein synthesis and VSMC hypertrophy. These data demonstrated that : (1)angII-induced Mnk1 activation is mediated by the Ras-ERK cascade in VSMC, and (2)Mnk1 is involved in angII-mediated protein synthesis and hypertrophy, presumably through the activation of translation-initiation.Hydrogen peroxide potently activated Mnk1 via ERK, p38MAP kinase and c-Src-dependent mechanisms. Mnk1 activated by oxidative stress translocated into the nucleus, indicating undefined functions of Mnk1.2D-gel electrophoresis revealed that several spots for phospho-proteins were increased in VSMC transfected with active Mnk1, suggesting the existence of novel Mnk1 substrates in the nucleus.In summary, Mnk1 may provide new insights into molecular mechanisms involved in cardiovascular remodeling.