期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 107, 期 8, 页码 967-974出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI12083
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资金
- NCRR NIH HHS [P40RR12358] Funding Source: Medline
- NHLBI NIH HHS [R37 HL050560, HL50560, R37 HL061690, R01 HL050560, R01 HL061690, HL61690] Funding Source: Medline
The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including beta -adrenergic receptor (beta AR) blockade. This was once viewed as counterintuitive, because acute administration causes myocardial depression. Cardiac myocytes from failing hearts show changes in beta AR signaling and excitation-contraction coupling that can impair cardiac contractility but the role of these abnormalities in the progression of heart failure is controversial. We therefore tested the impact of different manipulations that increase contractility on the progression of cardiac dysfunction in a mouse model of hypertrophic cardiomyopathy. High-level overexpression of the beta (2)AR caused rapidly progressive cardiac failure in this model. In contrast, phospholamban ablation prevented systolic dysfunction and exercise intolerance, but not hypertrophy, in hypertrophic cardiomyopathy mice. Cardiac expression of a peptide inhibitor of the beta AR kinase 1 not only prevented systolic dysfunction and exercise intolerance but also decreased cardiac remodeling and hypertrophic gene expression. These three manipulations of cardiac contractility had distinct effects on disease progression, suggesting that selective modulation of particular aspects of PAR signaling or excitation-contraction coupling can provide therapeutic benefit.
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