The alpha-1A adrenergic receptor regulates mitochondrial oxidative metabolism in the mouse heart
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY(2024)
摘要
Aims: The sympathetic nervous system regulates numerous critical aspects of mitochondrial function in the heart through activation of adrenergic receptors (ARs) on cardiomyocytes. Mounting evidence suggests that alpha 1-ARs, particularly the alpha 1A subtype, are cardioprotective and may mitigate the deleterious effects of chronic beta-AR activation by shared ligands. The mechanisms underlying these adaptive effects remain unclear. Here, we tested the hypothesis that alpha 1A-ARs adaptively regulate cardiomyocyte oxidative metabolism in both the uninjured and infarcted heart. Methods: We used high resolution respirometry, fatty acid oxidation (FAO) enzyme assays, substrate-specific electron transport chain (ETC) enzyme assays, transmission electron microscopy (TEM) and proteomics to characterize mitochondrial function comprehensively in the uninjured hearts of wild type and alpha 1A-AR knockout mice and defined the effects of chronic beta-AR activation and myocardial infarction on selected mitochondrial functions. Results: We found that isolated cardiac mitochondria from alpha 1A-KO mice had deficits in fatty acid-dependent respiration, FAO, and ETC enzyme activity. TEM revealed abnormalities of mitochondrial morphology characteristic of these functional deficits. The selective alpha 1A-AR agonist A61603 enhanced fatty-acid dependent respiration, fatty acid oxidation, and ETC enzyme activity in isolated cardiac mitochondria. The beta-AR agonist isoproterenol enhanced oxidative stress in vitro and this adverse effect was mitigated by A61603. A61603 enhanced ETC Complex I activity and protected contractile function following myocardial infarction. Conclusions: Collectively, these novel findings position alpha 1A-ARs as critical regulators of cardiomyocyte metabolism in the basal state and suggest that metabolic mechanisms may underlie the protective effects of alpha 1A-AR activation in the failing heart.
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关键词
Receptors,Adrenergic,Alpha,Mitochondria,Heart,Basal metabolism,Oxidative phosphorylation,Lipid metabolism
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