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 I Shih; Hsiao-Ying S Huang; Philip M Swigart; Bat E Myagmar; Paul C Simpson; Joseph S Rossi; Jonathan C Schisler; Brian C Jensen

doi:10.1016/j.jacbts.2023.08.013

Cardiomyocyte Alpha-1A Adrenergic Receptors Mitigate Postinfarct Remodeling and Mortality by Constraining Necroptosis

JACC Basic Transl Sci. 2023 Nov 15;9(1):78-96. doi: 10.1016/j.jacbts.2023.08.013. eCollection 2024 Jan.

Authors

Jiandong Zhang^{1

2}, Peyton B Sandroni^{2

3}, Wei Huang², Xiaohua Gao⁴, Leah Oswalt², Melissa A Schroder², SungHo Lee⁵, Yen-Yu I Shih⁵, Hsiao-Ying S Huang⁶, Philip M Swigart^{3

7}, Bat E Myagmar^{3

7}, Paul C Simpson^{3

7}, Joseph S Rossi¹, Jonathan C Schisler^{2

8}, Brian C Jensen^{1

2

8}

Affiliations

¹ Division of Cardiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
² UNC McAllister Heart Institute, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
³ Department of Medicine, University of California-San Francisco, San Francisco, California, USA.
⁴ Department of Epidemiology, University of North Carolina Gillings School of Public Health, Chapel Hill, North Carolina, USA.
⁵ Center for Animal MRI, University of North Carolina, Chapel Hill, North Carolina, USA.
⁶ Mechanical and Aerospace Engineering Department, North Carolina State University, Raleigh, North Carolina, USA.
⁷ San Francisco VA Medical Center, San Francisco, California, USA.
⁸ Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA.

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.

Keywords: adrenergic alpha; adrenergic α1 receptor antagonists; myocardial infarction; necroptosis; receptors.