Cardiomyocyte Alpha-1A Adrenergic Receptors Mitigate Postinfarct Remodeling and Mortality by Constraining Necroptosis
Jiandong Zhang, Peyton B. Sandroni, Wei Huang, Xiaohua Gao, Leah Oswalt, Melissa A. Schroder, Sungho Lee, Yen‐Yu Ian Shih, Hsiao‐Ying Shadow Huang, Philip M. Swigart, Bat E. Myagmar, Paul Simpson, Joseph S. Rossi, Jonathan C. Schisler, Brian C. Jensen
Abstract
Clinical studies have shown that α1-adrenergic receptor antagonists (α-blockers) are associated with increased heart failure risk. The mechanism underlying that hazard and whether it arises from direct inhibition of cardiomyocyte α1-ARs or from systemic effects remain unclear. To address these issues, we created a mouse with cardiomyocyte-specific deletion of the α1A-AR subtype and found that it experienced 70% mortality within 7 days of myocardial infarction driven, in part, by excessive activation of necroptosis. We also found that patients taking α-blockers at our center were at increased risk of death after myocardial infarction, providing clinical correlation for our translational animal models.