IKACh is constitutively active via PKC epsilon in aging mediated atrial fibrillation
Mengmeng Chang,
Kirin D. Gada,
Bojjibabu Chidipi,
Athanasios Tsalatsanis,
Justin Gibbons,
Elizabeth Remily-Wood,
Diomedes E. Logothetis,
Jenna Oberstaller,
Sami F. Noujaim
Affiliations
Mengmeng Chang
Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Kirin D. Gada
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Science, Bouvé College of Health Sciences, Center for Drug Discovery, Northeastern University, Boston, MA 02115, USA
Bojjibabu Chidipi
Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Athanasios Tsalatsanis
College of Medicine Office of Research, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Justin Gibbons
Center for Global Health and Infectious Diseases Research and USF Genomics Program, College of Public Health, University of South Florida, Tampa, FL 33612, USA
Elizabeth Remily-Wood
Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Diomedes E. Logothetis
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Science, Bouvé College of Health Sciences, Center for Drug Discovery, Northeastern University, Boston, MA 02115, USA
Jenna Oberstaller
Center for Global Health and Infectious Diseases Research and USF Genomics Program, College of Public Health, University of South Florida, Tampa, FL 33612, USA
Sami F. Noujaim
Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; Corresponding author
Summary: Atrial fibrillation (AF), the most common abnormal heart rhythm, is a major cause for stroke. Aging is a significant risk factor for AF; however, specific ionic pathways that can elucidate how aging leads to AF remain elusive. We used young and old wild-type and PKC epsilon- (PKCϵ) knockout mice, whole animal, and cellular electrophysiology, as well as whole heart, and cellular imaging to investigate how aging leads to the aberrant functioning of a potassium current, and consequently to AF facilitation. Our experiments showed that knocking out PKCϵ abrogates the effects of aging on AF by preventing the development of a constitutively active acetylcholine sensitive inward rectifier potassium current (IKACh). Moreover, blocking this abnormal current in the old heart reduces AF inducibility. Our studies demonstrate that in the aging heart, IKACh is constitutively active in a PKCϵ-dependent manner, contributing to the perpetuation of AF.
