期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 22, 期 12, 页码 4124-4135出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.22.12.4124-4135.2002
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资金
- NCRR NIH HHS [P40RR12358] Funding Source: Medline
- NHLBI NIH HHS [HL06308, T32 HL007382, HL07382, HL64018, R01 HL026057, P50 HL052318, R37 HL026057, HL52318, HL26057, R01 HL064018] Funding Source: Medline
- NIDA NIH HHS [DA10044, P01 DA010044] Funding Source: Medline
- NIDDK NIH HHS [R01 DK036569, DK36569] Funding Source: Medline
- NIMH NIH HHS [P01 MH040899, MH40899] Funding Source: Medline
Increases in type 1 phosphatase (PP1) activity have been observed in end stage human heart failure, but the role of this enzyme in cardiac function is unknown. To elucidate the functional significance of increased PP1 activity, we generated models with (i) overexpression of the catalytic subunit of PP1 in murine hearts and (ii) ablation of the PP1-specific inhibitor. Overexpression of PP1 (threefold) was associated with depressed cardiac function, dilated cardiomyopathy, and premature mortality, consistent with heart failure. Ablation of the inhibitor was associated with moderate increases in PP1 activity (23%) and impaired beta-adrenergic contractile responses. Extension of these findings to human heart failure indicated that the increased PP1 activity may be partially due to dephosphorylation or inactivation of its inhibitor. Indeed, expression of a constitutively active inhibitor was associated with rescue of beta-adrenergic responsiveness in failing human myocytes. Thus, PP1 is an important regulator of cardiac function, and inhibition of its activity may represent a novel therapeutic target in heart failure.
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