期刊
BASIC RESEARCH IN CARDIOLOGY
卷 105, 期 5, 页码 573-581出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00395-010-0106-3
关键词
Protein phosphatase 1 inhibitor-1; Cardiomyocytes; Apoptosis; ERK; Bad
资金
- NIH [HL-26507, HL-64018, HL-77101, HL-087861]
- Leducq Foundation
- AHA [0525435B]
Cardiac apoptosis has been considered an important contributing factor to heart failure. Several subcellular mechanisms, including increased protein phosphatase 1 activity, have been suggested to induce apoptosis. Protein phosphatase 1 is regulated by an endogenous inhibitor-1 (I-1) that is activated upon phosphorylation at threonine 35 via protein kinase A. Here, we tested whether cardiac-specific overexpression of a constitutively active (T35D, AA 1-65) inhibitor-1 (I-1c), could also affect cardiac apoptosis and heart failure progression induced by prolonged beta-adrenergic stimulation. We found that either acute or chronic expression of I-1c reduced isoproterenol (ISO)-induced apoptosis assessed by nuclear condensation, TUNEL staining and DNA fragmentation. The beneficial effects of I-1c were associated with increased expression of the anti-apoptotic protein Bcl-2, decreased expression of the pro-apoptotic protein Bax and reduced levels of active caspases as well as increased activation of ERK. These findings suggest that mitochondrial signaling and ERK activation may be involved in the I-1c cardioprotective effects against apoptosis induced by prolonged beta-adrenergic stimulation.
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