Frontiers in Cardiovascular Medicine | |
β-Adrenergic Receptor Desensitization/Down-Regulation in Heart Failure: A Friend or Foe? | |
article | |
Abrahim Mahmood1  Kinza Ahmed1  Youhua Zhang1  | |
[1] Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine | |
关键词: β-adrenergic receptor; β-adrenergic receptor desensitization/down-regulation; cardiac ryanodine receptor; calcium leak; arrhythmia; heart failure; | |
DOI : 10.3389/fcvm.2022.925692 | |
学科分类:地球科学(综合) | |
来源: Frontiers | |
【 摘 要 】
Cardiac sympathetic activation, mediated by β-adrenergic receptors (β-ARs), normally increases cardiac contraction and relaxation. Accomplishing this task requires a physiological, concerted Ca 2+ signaling, being able to increase Ca 2+ release from sarcoplasmic reticulum (SR) in systole and speed up Ca 2+ re-uptake in diastole. In heart failure (HF) myocardial β-ARs undergo desensitization/down-regulation due to sustained sympathetic adrenergic activation. β-AR desensitization/down-regulation diminishes adrenergic signaling and cardiac contractile reserve, and is conventionally considered to be detrimental in HF progression. Abnormal Ca 2+ handling, manifested as cardiac ryanodine receptor (RyR2) dysfunction and diastolic Ca 2+ leak (due to sustained adrenergic activation) also occur in HF. RyR2 dysfunction and Ca 2+ leak deplete SR Ca 2+ store, diminish Ca 2+ release in systole and elevate Ca 2+ levels in diastole, impairing both systolic and diastolic ventricular function. Moreover, elevated Ca 2+ levels in diastole promote triggered activity and arrhythmogenesis. In the presence of RyR2 dysfunction and Ca 2+ leak, further activation of the β-AR signaling in HF would worsen the existing abnormal Ca 2+ handling, exacerbating not only cardiac dysfunction, but also ventricular arrhythmogenesis and sudden cardiac death. Thus, we conclude that β-AR desensitization/down-regulation may be a self-preserving, adaptive process (acting like an intrinsic β-AR blocker) protecting the failing heart from developing lethal ventricular arrhythmias under conditions of elevated sympathetic drive and catecholamine levels in HF, rather than a conventionally considered detrimental process. This also implies that medications simply enhancing β-AR signaling (like β-AR agonists) may not be so beneficial unless they can also correct dysfunctional Ca 2+ handling in HF.
【 授权许可】
CC BY
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