Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Dash, R; Schmidt, AG; Pathak, A; Gerst, MJ; Biniakiewicz, D; Kadambi, VJ; Hoit, BD; Abraham, WT; Kranias, EG.
Differential regulation of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertrophy.
Cardiovasc Res. 2003; 57(3): 704-714.
Doi: 10.1016/S0008-6363(02)00772-1
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- Co-Autor*innen der Med Uni Graz
- Schmidt Albrecht
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Blood Pressure -
- Calcium-Binding Proteins - genetics Calcium-Binding Proteins - 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 Muscle Cells - enzymology
- Norepinephrine - pharmacology Norepinephrine - physiology
- Sex Factors -
- Signal Transduction -
- Survival Rate -
- Ventricular Dysfunction, Left - physiopathology
- p38 Mitogen-Activated Protein Kinases -
- Find related publications in this database (Keywords)
- adrenergic (ant)agonists
- contractile function
- gender
- hypertrophy
- second messengers