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| Calcineurin promotes protein kinase C and c-Jun NH2-terminal kinase activation in the heart - Cross-talk between cardiac hypertrophic signaling pathways |
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| Author(s): De Windt LJ, Lim HW, Haq S, Force T, Molkentin JD |
| Source: JOURNAL OF BIOLOGICAL CHEMISTRY Volume: 275 Issue: 18 Pages: 13571-13579 Published: MAY 5 2000 |
| Times Cited: 136 References: 57 |
| Abstract: Multiple intracellular signaling pathways have been shown to regulate the hypertrophic growth of cardiomyocytes, Both necessary and sufficient roles have been described for the mitogen activated protein kinase (MAPR) signaling pathway, specific protein kinase C (PKC) isoforms, and calcineurin, Here we investigate the interdependence between calcineurin, MAPK, and PKC isoforms in regulating cardiomyocyte hypertrophy using three separate approaches. Hearts from hypertrophic calcineurin transgenic mice were characterized for PKC and MAPK activation. Transgenic hearts demonstrated activation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK1/2), but not p38 MAPK factors. Calcineurin transgenic hearts demonstrated increased activation of PKC alpha, beta(1), and theta, but not of epsilon, beta(2), or lambda. In a second approach, cultured cardiomyocytes were infected with a calcineurin adenovirus to induce hypertrophy and the effects of pharmacologic inhibitors or co-infection with a dominant negative adenovirus were examined. Calcineurin-mediated hypertrophy was prevented with PKC inhibitors, Ca2+ chelation, and attenuated with a dominant negative SEK-1 (MKK4) adenovirus, but inhibitors of ERK or p38 activation had no effect. In a third approach, we examined the activation of MAPK factors and PKC isoforms during the progression of load-induced hypertrophy in aortic banded rats with or without cyclosporine. We determined that inhibition of calcineurin activity with cyclosporine prevented PKC alpha, theta, and JNK activation, but did not affect PKC epsilon, beta, lambda, ERK1/2, or p38 activation. Collectively, these data indicate that calcineurin hypertrophic signaling is interconnected with PKC alpha, theta, and JNK in the heart, while PKC epsilon, beta, lambda, p38, and ERK1/2 are not involved in calcineurin-mediated hypertrophy. |
| Document Type: Article |
| Language: English |
| Reprint Address: Molkentin, JD (reprint author), Univ Cincinnati, Childrens Hosp, Med Ctr, Dept Pediat,Div Mol Cardiovasc Biol, 3333 Burnet Ave, Cincinnati, OH 45229 USA |
Addresses:
1. Univ Cincinnati, Childrens Hosp, Med Ctr, Dept Pediat,Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA
2. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr,Dept Med, Charlestown, MA 02129 USA |
| Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA |
| Subject Category: Biochemistry & Molecular Biology |
| IDS Number: 312CH |
| ISSN: 0021-9258 |
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