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Basic Res Cardiol. 2016 May;111(3):28. doi: 10.1007/s00395-016-0542-9. Epub 2016 Mar 29.

Electrophysiology and metabolism of caveolin-3-overexpressing mice.

Author information

  • 1Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
  • 2Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA.
  • 3Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
  • 4Department of Pediatrics, Sharp Rees-Stealy Medical Group, San Diego, CA, USA.
  • 5Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.
  • 6Department of Medicine, Cellular and Molecular Arrhythmia Research Program, University of Wisconsin, Madison, WI, USA.
  • 7Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  • 8Veterans Affairs San Diego Healthcare System, San Diego, CA, USA. droth@ucsd.edu.
  • 9Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA. droth@ucsd.edu.

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.

KEYWORDS:

Cardiac conduction; Caveolae; Caveolin-3; Heart rate; Kv channels

PMID:
27023865
DOI:
10.1007/s00395-016-0542-9
[PubMed - indexed for MEDLINE]
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