Differential regulation of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertrophy

作者：Dash R; Schmidt AG; Pathak A; Gerst MJ; Biniakiewicz D; Kadambi VJ; Hoit BD; Abraham WT; Kranias EG^*

来源：Cardiovascular Research, 2003, 57(3): 704-714.

DOI：10.1016/S0008-6363(02)00772-1

• adrenergic (ant)agonists
• contractile function
• gender
• hypertrophy
• second messengers

Objective: Exogenous catecholamine exposure has been associated with p38 mitogen-activated protein kinase (MAPK) and cardiac hypertrophy. In this study, we investigated the regulation of p38 MAPK in cardiac remodeling elicited by endogenous adrenergic mechanisms. Methods: Transgenic male and female mice with fourfold phospholamban (PLB) overexpression exhibited enhanced circulating norepinephrine (NE). as a physiological compensatory mechanism to attenuate PLB's inhibitory effects. This enhanced noradrenergic state resulted in left ventricular hypertrophy/dilatation and depressed function. Results: Male transgenics exhibited ventricular hypertrophy and mortality at 15 months, concurrent with cardiac p38 MAPK activation. Female transgenics, despite similar contractile dysfunction, displayed a temporal delay in p38 activation, hypertrophy, and mortality (22 months), which was associated with sustained cardiac levels of MAP Kinase Phosphatase-1 (MKP-1), a potent inhibitor of p38. At 22 months, decreases in cardiac MKP-1 were accompanied by increased levels of p38 activation. In vitro studies indicated that preincubation with 17-beta-estradiol induced high MKP-1 levels, which precluded NE-induced p38 activation. Conclusion: These findings suggest that norepinephrine-induced hypertrophy is linked closely with p38 MAP kinase activation, which can be endogenously modulated through estrogen-responsive regulation of MKP-1 expression.

• 出版日期2003-3