Cardiomyocyte alpha-1A adrenergic receptors mitigate post-infarct remodeling and mortality by constraining necroptosis

Zhang, J.; Sandroni, P. B.; Huang, W.; Oswalt, L.; Smith, A. J.; Ash, T.; Lee, S.-H.; Shih, Y.-Y. I.; Huang, H.-Y. S.; Myagmar, B.-E.; Schisler, J. C.; Jensen, B. C.

doi:10.1101/2022.08.29.505687

bioRxiv · 10.1101/2022.08.29.505687

Cardiomyocyte alpha-1A adrenergic receptors mitigate post-infarct remodeling and mortality by constraining necroptosis

Zhang, J.·Sandroni, P. B.·Huang, W.·Oswalt, L.·Smith, A. J.·Ash, T.·Lee, S.-H.·Shih, Y.-Y. I.·Huang, H.-Y. S.·Myagmar, B.-E.·Schisler, J. C.·Jensen, B. C.

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Abstract

Activation of alpha-1-adrenergic receptors (1-ARs), particularly the 1A subtype, protects the murine heart against injury, whereas human studies show that 1-AR antagonists (-blockers) may increase the risk of heart failure. We created a cardiomyocyte-specific 1A-AR knockout mouse (cmAKO) to define the mechanisms underlying these effects and to elucidate whether they arise from cardiomyocyte 1A-ARs or systemic factors. Myocardial infarction (MI) resulted in 70% 7-day mortality in cmAKO compared to 10% in wild type (WT) mice. cmAKO mice exhibited exaggerated ventricular remodeling and increased cell death compared to WT mice 3 days post-MI, coupled to upregulation of canonical mediators of necroptosis: receptor-interacting protein (RIP) kinases RIP1 and RIP3 and mixed lineage kinase domain-like protein. An 1A-AR agonist mitigated ischemia-induced cardiomyocyte death and necroptotic signaling in vitro. A RIP1 antagonist abrogated the protective effects of 1A activation in vivo and in vitro. We found that patients at our center who were taking -blockers at the time of MI experienced a higher risk of mortality (hazard ratio 1.53, p=0.029) during 5-year follow-up, providing clinical correlation for our experimental data. Collectively our findings indicate that cardiomyocyte 1A-ARs constrain ischemia-induced necroptosis and suggest caution in the use of -blockers in patients at risk for MI.

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Zhang, J., Sandroni, P. B., Huang, W., Oswalt, L., Smith, A. J., Ash, T., Lee, S.-H., Shih, Y.-Y. I., Huang, H.-Y. S., Myagmar, B.-E., Schisler, J. C., Jensen, B. C.. 2022-08-29. Cardiomyocyte alpha-1A adrenergic receptors mitigate post-infarct remodeling and mortality by constraining necroptosis. https://doi.org/10.1101/2022.08.29.505687

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