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


CONCLUSIONS
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.
Dash
Rajesh
R
Department of Pharmacology and Cell Biophysics, University of Cincinnati, OH 45267-0575, USA.
Schmidt
Albrecht G
AG
Pathak
Anand
A
Gerst
Michael J
MJ
Biniakiewicz
Danuta
D
Kadambi
Vivek J
VJ
Hoit
Brian D
BD
Abraham
William T
WT
Kranias
Evangelia G
EG
D000818:Animals; D001794:Blood Pressure; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000502:physiology; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D032342:Muscle Cells / Q000187:drug effects / Q000201:enzymology; D009638:Norepinephrine / Q000494:pharmacology / Q000502:physiology*; D012737:Sex Factors; D015398:Signal Transduction; D015996:Survival Rate; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*; D048051:p38 Mitogen-Activated Protein Kinases; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D004958:Estradiol; D020928:Mitogen-Activated Protein Kinases; D009638:Norepinephrine; D048051:p38 Mitogen-Activated Protein Kinases; D000099211:Phospholamban