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

Abstract

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.

• Authors: Rajesh Dash, Albrecht G Schmidt, Anand Pathak, Michael J Gerst, Danuta Biniakiewicz, Vivek J Kadambi, Brian D Hoit, William T Abraham, Evangelia G Kranias
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 57 Issue 3 Pg. 704-14 (Mar 2003) ISSN: 0008-6363 [Print] England
• PMID: 12618232 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Calcium-Binding Proteins
• phospholamban
• Estradiol
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Calcium-Transporting ATPases
• Norepinephrine

Topics

• Animals
• Blood Pressure
• Calcium-Binding Proteins (genetics, metabolism)
• Calcium-Transporting ATPases (physiology)
• Cells, Cultured
• Estradiol (pharmacology)
• Female
• Hypertrophy, Left Ventricular (physiopathology)
• Male
• Mice
• Mice, Transgenic
• Mitogen-Activated Protein Kinases (physiology)
• Muscle Cells (drug effects, enzymology)
• Norepinephrine (pharmacology, physiology)
• Sex Factors
• Signal Transduction
• Survival Rate
• Ventricular Dysfunction, Left (physiopathology)
• p38 Mitogen-Activated Protein Kinases