Decreased long-chain acyl-CoA dehydrogenase mediates cardiac energy deficiency and injury induced by β-adrenergic stimulation

Abstract Background: Overactivation of β-adrenergic receptor (β-AR) signaling underlies the cardiotoxic effects of sympathetic hyperactivity in cardiovascular disease. However, the mechanism through which metabolic changes caused by β-AR overactivation leads to cardiac injury is poorly understood. Methods: A comprehensive multi-omics profile was performed on myocardial tissue following exposure to isoproterenol (ISO, a β-AR agonist). Cardiac-specific overexpression or downregulation of the relevant metabolic enzyme was established to investigate the mechanism. During ISO stimulation, profiles for substrate oxidation and ATP production in cardiomyocytes were also examined. Results: Through a non-targeted metabolomics approach, lipids were identified as the most significantly affected metabolites in mouse hearts following β-AR overactivation, and subsequent targeted lipidomics analysis revealed that acylcarnitine levels were most notably elevated. Consistent with these results, patients with acute coronary syndrome showed a higher circulating acylcarnitine profile which correlated with catecholamine levels and cardiac pathologies. Mechanistic studies found that excess acylcarnitine exposure triggered inflammasome-dependent cardiomyocyte pyroptosis. Expression level of long-chain acyl-coenzyme A dehydrogenase (LCAD), an enzyme that metabolizes acylcarnitines, was markedly decreased in cardiomyocytes upon β-AR overactivation. Furthermore, ISO inhibited LCAD enzymatic activity by inhibiting sirtuin 3-mediated deacetylation, leading to ATP deficiency and acylcarnitine accumulation. Activation of AMP-activated protein kinase (AMPK) attenuated the effects of ISO on cardiomyocytes that reduced LCAD, ATP depletion, acylcarnitine-induced pyroptosis, and cardiac dysfunction in vivo. Conclusions: Upon β-AR overactivation, decreased LCAD in cardiomyocytes leads to energy deficiency and pyroptosis, subsequently impair cardiac function. Upregulation of LCAD by AMPK activators may be a therapeutic strategy for treating sympathetic stress-induced cardiac injury.