THE ALPHA-1A ADRENERGIC RECEPTOR REGULATES OXIDATIVE METABOLISM IN THE MOUSE HEART

The sympathetic nervous system regulates critical aspects of mitochondrial function in the heart through activation of adrenergic receptors (ARs) on cardiomyocytes. Widespread use of α1-blockers for the treatment of benign prostatic hyperplasia is associated with increased risk of heart failure (HF). 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 endogenous catecholamine ligands. However, the mechanisms through which α1A-ARs exert their cardioprotective effects remain unclear. Here, we tested the hypothesis that α1A-ARs adaptively regulate cardiomyocyte oxidative metabolism in both the injured and infarcted heart. We utilize global and cardiomyocyte-specific knockout models to characterize the effects of α1A-AR genetic deletion on mitochondrial function and metabolism using respirometry, substrate-specific electron transport (ETC) enzyme assays, transmission electron microscopy, and proteomics. We then compared the effects α1A- and β-AR agonist treatment on mitochondrial function in vivo and in vitro. We found that isolated cardiac mitochondria from α1A-KO mice exhibit deficits in fatty acid-dependent respiration and ETC capacity that coincide with abnormal mitochondrial morphology. Cardiomyocyte-specific α1A-AR genetic deletion disproportionately alters transcript abundance of mitochondrial proteins responsible for OXPHOS, and these effects were exacerbated by myocardial infarction (MI). In contrast, the selective α1A-AR agonist A61603 enhanced both fatty acid oxidation (FAO) and ETC enzyme activities. The β-AR agonist isoproterenol enhanced oxidative stress in vitro, and this effect was mitigated by A61603. A61603 enhanced ETC Complex I capacity, FAO gene expression, and cardiac contractility following MI. Collectively, these findings position α1A-ARs as critical regulators of cardiomyocyte metabolism. Additionally, they suggest that enhanced mitochondrial metabolism may underlie the protective effects of α1A-AR activation in HF. Our findings suggest that widespread use α1-blockers in patients with cardiovascular risk should be reconsidered, and subtype specificity may be needed. In contrast, selective α1A-AR agonists show distinct potential as novel HF therapeutics.