title: Electrophysiology and metabolism of caveolin-3-overexpressing mice.
abstract: Caveolin-3 (Cav-3) plays a critical role in organizing signaling molecules and ion channels involved in cardiac conduction and metabolism. Mutations in Cav-3 are implicated in cardiac conduction abnormalities and myopathies. Additionally, cardiac-specific overexpression of Cav-3 (Cav-3 OE) is protective against ischemic and hypertensive injury, suggesting a potential role for Cav-3 in basal cardiac electrophysiology and metabolism involved in stress adaptation. We hypothesized that overexpression of Cav-3 may alter baseline cardiac conduction and metabolism. We examined: (1) ECG telemetry recordings at baseline and during pharmacological interventions, (2) ion channels involved in cardiac conduction with immunoblotting and computational modeling, and (3) baseline metabolism in Cav-3 OE and transgene-negative littermate control mice. Cav-3 OE mice had decreased heart rates, prolonged PR intervals, and shortened QTc intervals with no difference in activity compared to control mice. Dobutamine or propranolol did not cause significant changes between experimental groups in maximal (dobutamine) or minimal (propranolol) heart rate. Cav-3 OE mice had an overall lower chronotropic response to atropine. The expression of Kv1.4 and Kv4.3 channels, Nav1.5 channels, and connexin 43 were increased in Cav-3 OE mice. A computational model integrating the immunoblotting results indicated shortened action potential duration in Cav-3 OE mice linking the change in channel expression to the observed electrophysiology phenotype. Metabolic profiling showed no gross differences in VO2, VCO2, respiratory exchange ratio, heat generation, and feeding or drinking. In conclusion, Cav-3 OE mice have changes in ECG intervals, heart rates, and cardiac ion channel expression. These findings give novel mechanistic insights into previously reported Cav-3 dependent cardioprotection.
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.|Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Schilling
authors.affiliation: Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.|Department of Pediatrics, Sharp Rees-Stealy Medical Group, San Diego, CA, USA.
authors.forename: Yousuke T
authors.initials: YT
authors.lastname: Horikawa
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.|Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Alice E
authors.initials: AE
authors.lastname: Zemljic-Harpf
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Vincent
authors.affiliation: Department of Medicine, Cellular and Molecular Arrhythmia Research Program, University of Wisconsin, Madison, WI, USA.
authors.forename: Leonid
authors.initials: L
authors.lastname: Tyan
authors.affiliation: Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Judith K
authors.initials: JK
authors.lastname: Yu
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.|Department of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
authors.affiliation: Department of Medicine, Cellular and Molecular Arrhythmia Research Program, University of Wisconsin, Madison, WI, USA.
authors.forename: Ravi C
authors.initials: RC
authors.lastname: Balijepalli
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.|Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA.
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
authors.affiliation: Veterans Affairs San Diego Healthcare System, San Diego, CA, USA. droth@ucsd.edu.|Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA. droth@ucsd.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Roth
mesh_terms: D000818:Animals; D051244:Caveolin 3 / Q000378:metabolism*; D003198:Computer Simulation; D004562:Electrocardiography; D006321:Heart / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*
chemical_list: D051244:Caveolin 3
keywords: Cardiac conduction; Caveolae; Caveolin-3; Heart rate; Kv channels