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 α1-ARs, particularly the α1A subtype, are cardioprotective and may mitigate the deleterious effects of chronic β-AR activation by shared ligands. The mechanisms underlying these adaptive effects remain unclear. Here, we tested the hypothesis that α1A-ARs adaptively regulate cardiomyocyte oxidative metabolism in both the uninjured and infarcted heart. 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 α1A-AR knockout mice and defined the effects of chronic β-AR activation and myocardial infarction on selected mitochondrial functions. We found that isolated cardiac mitochondria from α1A-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 α1A-AR agonist A61603 enhanced fatty-acid dependent respiration, fatty acid oxidation, and ETC enzyme activity in isolated cardiac mitochondria. The β-AR agonist isoproterenol enhanced oxidative stress and this adverse effect was mitigated by A61603. A61603 enhanced ETC Complex I activity and protected contractile function following myocardial infarction. Collectively, these novel findings position α1A-ARs as critical regulators of cardiomyocyte metabolism in the basal state and suggest that metabolic mechanisms may underlie the protective effects of α1A-AR activation in the failing heart.

中文翻译：

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α-1A 肾上腺素受体调节小鼠心脏线粒体氧化代谢

交感神经系统通过激活心肌细胞上的肾上腺素能受体（AR）来调节心脏线粒体功能的许多关键方面。越来越多的证据表明，α1-AR，特别是 α1A 亚型，具有心脏保护作用，并且可以减轻共享配体慢性 β-AR 激活的有害影响。这些适应性效应背后的机制仍不清楚。在这里，我们测试了以下假设：α1A-AR 适应性调节未受伤​​和梗塞心脏中的心肌细胞氧化代谢。我们使用高分辨率呼​​吸测定法、脂肪酸氧化 (FAO) 酶测定、底物特异性电子传递链 (ETC) 酶测定、透射电子显微镜 (TEM) 和蛋白质组学来全面表征野生型和 α1A- 未受伤心脏中的线粒体功能。 AR 基因敲除小鼠并确定了慢性 β-AR 激活和心肌梗塞对选定线粒体功能的影响。我们发现从 α1A-KO 小鼠分离的心脏线粒体在脂肪酸依赖性呼吸、FAO 和 ETC 酶活性方面存在缺陷。TEM 揭示了这些功能缺陷所特有的线粒体形态异常。选择性 α1A-AR 激动剂 A61603 增强离体心脏线粒体中的脂肪酸依赖性呼吸、脂肪酸氧化和 ETC 酶活性。β-AR 激动剂异丙肾上腺素会增强氧化应激，而 A61603 可以减轻这种不利影响。A61603 增强 ETC 复合物 I 活性并保护心肌梗塞后的收缩功能。总的来说，这些新发现将 α1A-AR 定位为基础状态下心肌细胞代谢的关键调节因子，并表明代谢机制可能是 α1A-AR 激活对衰竭心脏的保护作用的基础。