The alpha-1A adrenergic receptor regulates mitochondrial oxidative metabolism in the mouse heart.
J Mol Cell Cardiol
; 187: 101-117, 2024 02.
Article
in En
| MEDLINE
| ID: mdl-38331556
ABSTRACT
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 α1-ARs, particularly the α1A subtype, are cardioprotective and may mitigate the deleterious effects of chronic ß-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.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 α1A-AR knockout mice and defined the effects of chronic ß-AR activation and myocardial infarction on selected mitochondrial functions.RESULTS:
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 ß-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 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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Myocardial Contraction
/
Myocardial Infarction
Limits:
Animals
Language:
En
Journal:
J Mol Cell Cardiol
/
J. mol. cell. cardiol
/
Journal of molecular and cellular cardiology
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: