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

Pavelec, C. M.; Young, A.; Luviano, H. L.; Orrell, E. E.; Poudel, N.; Wolpe, A. G.; Thomas, S. H.; Yeudall, S.; Upchurch, C.; Okusa, M. D.; Isakson, B. E.; Wolf, M. J.; Leitinger, N.

doi:10.1101/2023.12.29.573679

bioRxiv · 10.1101/2023.12.29.573679

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

Pavelec, C. M.·Young, A.·Luviano, H. L.·Orrell, E. E.·Poudel, N.·Wolpe, A. G.·Thomas, S. H.·Yeudall, S.·Upchurch, C.·Okusa, M. D.·Isakson, B. E.·Wolf, M. J.·Leitinger, N.

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Abstract

Pannexin 1 (PANX1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial infarction. However, a possible role of PANX1 in cardiomyocytes in the progression of heart failure has not yet been investigated. We generated a novel mouse line with constitutive deletion of PANX1 in cardiomyocytes (Panx1MyHC6). PANX1 deletion in cardiomyocytes had no effect on unstressed heart function but increased the glycolytic metabolism both in vivo and in vitro. In vitro, treatment of H9c2 cardiomyocytes with isoproterenol led to PANX1-dependent release of ATP and Yo-Pro-1 uptake, as assessed by pharmacological blockade with spironolactone and siRNA-mediated knock-down of PANX1. To investigate non-ischemic heart failure and the preceding cardiac hypertrophy we administered isoproterenol, and we demonstrate that Panx1MyHC6 mice were protected from systolic and diastolic left ventricle volume increases and cardiomyocyte hypertrophy. Moreover, we found that Panx1MyHC6 mice showed decreased isoproterenol-induced recruitment of immune cells (CD45+), particularly neutrophils (CD11b+, Ly6g+), to the myocardium. Together these data demonstrate that PANX1 deficiency in cardiomyocytes impacts glycolytic metabolism and protects against cardiac hypertrophy in non-ischemic heart failure at least in part by reducing immune cell recruitment. Our study implies PANX1 channel inhibition as a therapeutic approach to ameliorate cardiac dysfunction in heart failure patients.

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Pavelec, C. M., Young, A., Luviano, H. L., Orrell, E. E., Poudel, N., Wolpe, A. G., Thomas, S. H., Yeudall, S., Upchurch, C., Okusa, M. D., Isakson, B. E., Wolf, M. J., Leitinger, N.. 2023-12-30. Pannexin 1 Channels Control Cardiomyocyte Metabolism and Neutrophil Recruitment During Non-Ischemic Heart Failure. https://doi.org/10.1101/2023.12.29.573679

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