© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Differential regulation of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertrophy
aDepartment of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, OH 45267, USA
bDepartment of Cardiology and Pneumology, University of Goettingen, Goettingen, Germany
cDepartment of Internal Medicine, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA
dDepartment of Cardiovascular Biology, Millennium Pharmaceuticals Inc., Cambridge, MA 02139, USA
eDepartment of Internal Medicine, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44195, USA
fDepartment of Internal Medicine; University of Kentucky, College of Medicine, Lexington, KY 40536, USA
litsa.kranias{at}uc.edu
* Corresponding author. Present address: Department of Pharmacology and Cell Biophysics, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. Tel.: +1-513-558-2377; fax: +1-513-558-2269.
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-β-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.
KEYWORDS Adrenergic (ant)agonists; Contractile function; Gender; Hypertrophy; Second messengers
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