Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 86, Issue -, Pages 23-31Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2015.06.012
Keywords
t-tubules; Ca imaging; Heart failure
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Funding
- British Heart Foundation [PG/10/91/28644, RG/12/10/29802]
- British Heart Foundation [RG/12/10/29802, PG/10/91/28644] Funding Source: researchfish
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In mammalian cardiac ventricular myocytes, Ca influx and release occur predominantly at t-tubules, ensuring synchronous Ca release throughout the cell. Heart failure is associated with disrupted t-tubule structure, but its effect on t-tubule function is less clear. We therefore investigated Ca influx and release at the t-tubules of ventricular myocytes isolated from rat hearts similar to 18 weeks after coronary artery ligation (CAL) or corresponding Sham operation. L-type Ca current (I-Ca) was recorded using the whole-cell voltage-clamp technique in intact and detubulated myocytes; Ca release at t-tubules was monitored using confocal microscopy with voltage- and Ca-sensitive fluorophores. CAL was associated with cardiac and cellular hypertrophy, decreased ejection fraction, disruption oft-tubule structure and a smaller, slower Ca transient, but no change in ryanodine receptor distribution, L-type Ca channel expression, or I-Ca density. In Sham myocytes, I-Ca was located predominantly at the t-tubules, while in CAL myocytes, it was uniformly distributed between the t-tubule and surface membranes. Inhibition of protein kinase A with H-89 caused a greater decrease oft-tubular I-Ca in CAL than in Sham myocytes; in the presence of H-89, t-tubular I-Ca density was smaller in CAL than in Sham myocytes. The smaller t-tubular in CAL myocytes was accompanied by increased latency and heterogeneity of SR Ca release at t-tubules, which could be mimicked by decreasing I-Ca using nifedipine. These data show that CAL decreases t-tubular I-Ca via a PKA-independent mechanism, thereby impairing Ca release at t-tubules and contributing to the altered excitation-contraction coupling observed in heart failure. (C) 2015 The Authors. Published by Elsevier Ltd.
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