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

Activation of alpha-1-adrenergic receptors (α1-ARs), particularly the α1A subtype, protects the murine heart against injury, whereas human studies show that α1-AR antagonists (α-blockers) may increase the risk of heart failure. We created a cardiomyocyte-specific α1A-AR knockout mouse (cmAKO) to define the mechanisms underlying these effects and to elucidate whether they arise from cardiomyocyte α1A-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 α1A-AR agonist mitigated ischemia-induced cardiomyocyte death and necroptotic signaling in vitro . A RIP1 antagonist abrogated the protective effects of α1A activation in vivo and in vitro . We found that patients at our center who were taking α-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 α1A-ARs constrain ischemia-induced necroptosis and suggest caution in the use of α-blockers in patients at risk for MI.