Get started
Work

The Alpha-1a Adrenergic Receptor Regulates Oxidative Metabolism in the Mouse Heart

Year: 2025
Type: dissertation
Abstract: 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.
DOI: 10.17615/ztze-vt44
Language: English
Open Access status: green
OpenAlex ID: W7077498657
Cites:
Cited by:
Related to: