Wednesday, June 7, 2023
6/7/2023
The heart consumes more ATP than any other organ, the vast majority of which is generated by fatty acid oxidation (FAO) coupled to oxidative phosphorylation (OXPHOS) in mitochondria. The sympathetic nervous system (SNS) regulates numerous aspects of mitochondrial function through activation of alpha-1-adrenergic receptors (a1-ARs) and beta-ARs (ß-ARs) in cardiomyocytes, as we recently reviewed. Persistent stimulation of cardiac ß-ARs causes pathological structural and metabolic changes resulting in myocardial energy depletion and heart failure (HF), but a1-ARs exert adaptive effects in the failing heart, mitigating the toxicity of chronic ß-AR activation. The mechanisms underlying this cardioprotection remain largely unclear. There are three a1-AR subtypes: A, B, and D. Mounting evidence indicates that the a1A subtype protects cardiomyocytes against multiple types of injury. We previously published that a selective a1A agonist increases ATP content in anthracycline-exposed failing mouse hearts. Our preliminary data now show that permeabilized cardiac muscle fibers and isolated mitochondria from knockout mice lacking the aA-AR (a1AKO) exhibit decreased FAO and diminished activity of electron transport chain (ETC) Complex I and II. We also recently found that treatment with a selective a1A agonist enhances Complex I, II and IV activity in uninjured mouse hearts and protects cardiac energetic capacity and contractile function in mice subjected to experimental myocardial infarction. Collectively, these findings suggest a novel mechanism for a1A-mediated cardioprotection, as regulation of neither FAO nor OXPHOS by ß1-ARs has been studied previously. We now propose three Specific Aims to build upon our published findings and novel preliminary data to test the central hypothesis that a1A-ARs metabolically support the uninjured heart and protect the failing heart by enhancing mitochondrial oxidative capacity. Aim 1 will determine whether a1A-ARs enhance OXPHOS in the heart through cardiomyocyte-autonomous effects using our cardiomyocyte-specific ß1A knockout mice, novel focused studies of a1A skeletal muscle FAO regulation, and a high fat diet model. Aim 2 will find if a1A-ARs preserve energetic capacity through maintenance of long chain FAO and regulation of ETC enzyme activity, coupling in vivo profiling of a1A knockout and a1A agonist treated mouse hearts with mechanistic in vitro approaches. Aim 3 will test whether selective a1A-AR agonists act as mitotropes—drugs that enhance mitochondrial function--to protect against HF using three clinically relevant mouse models: chronic isoproterenol infusion, cardiomyocyte-specific loss of FAO (Carnitine palmitoyl transferase 2 knockout), and a Duchenne Muscular Dystrophy model in which Complex I activity is impaired. If successfully completed, the proposed experiments have the potential to significantly expand our understanding of SNS regulation of cardiomyocyte mitochondrial function, elucidating new mechanisms of a1A-mediated cardioprotection in clinically and physiologically relevant mouse models. These studies also represent the next step in our ongoing efforts to advance a1A-AR agonists as novel HF therapies.
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