Pannexin 1 Channels Control Cardiomyocyte Metabolism and Neutrophil Recruitment During Non-Ischemic Heart Failure

Proper contractile function of the heart is central to life. At the cellular level availability of ATP to allow for proper contraction within the cardiomyocyte is required to ensure that synchronous beating occurs. Generating this ATP and maintaining a sufficient pool is necessary to keep this required physiological process running.
In the first part of this dissertation, we explore a novel role for pannexin 1 (PANX1) in regulating cardiomyocyte glycolytic metabolism and how the deletion of the channel in cardiomyocytes impacts disease onset during non-ischemic heart failure. We find that deletion of PANX1 in cardiomyocyte shifts cells to a hyper-glycolytic state at baseline and further simulation with a beta-adrenergic agonist does not raise glycolytic bioenergetics as observed in control cells. Additionally, we determined that cardiomyocyte specific deletion of PANX1 protects mice against isoproterenol induced hypertrophy and significantly decreases neutrophil infiltration into the myocardium.
In the second part of this dissertation, we seek to understand how oxidized lipids regulate the heart in a murine model of HFpEF induced by high fat high sucrose (HFHS) feeding. We determine that using a liver-inducible AAV8 to drive scFv- E06 expression we lower plasma oxidized phospholipids after HFHS feeding. Additionally, we find that scFv-E06 protects mice from cardiac and metabolic dysfunction induced by HFHS feeding. Finally, we explore potential mechanisms by which this may be occurring and that scFv-E06 expression may protect by different mechanisms in a sex-dependent manner.