β-Adrenergic Receptor Desensitization/Down-Regulation in Heart Failure: A Friend or Foe?

Autor:	Mahmood A; Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY, United States., Ahmed K; Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY, United States., Zhang Y; Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in cardiovascular medicine [Front Cardiovasc Med] 2022 Jul 01; Vol. 9, pp. 925692. Date of Electronic Publication: 2022 Jul 01 (Print Publication: 2022).
DOI:	10.3389/fcvm.2022.925692
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Mahmood, Ahmed and Zhang.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu