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Electrophysiology and metabolism of caveolin-3-overexpressing mice

  • Jan M. Schilling
  • Yousuke T. Horikawa
  • Alice E. Zemljic-Harpf
  • Kevin P. Vincent
  • Leonid Tyan
  • Judith K. Yu
  • Andrew D. McCulloch
  • Ravi C. Balijepalli
  • Hemal H. Patel
  • David M. Roth
Original Contribution

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

Caveolae Caveolin-3 Cardiac conduction Heart rate Kv channels 

Abbreviations

AKAP100

A-kinase anchoring protein

ANOVA

Analysis of variance

APD

Action potential duration

bpm

Beats per minute

CO2

Carbon dioxide

Cav-3

Caveolin-3

CaT

Calcium transients

Cx43

Connexin 43

ECG

Electrocardiogram

EDTA

Ethylenediaminetetraacetic acid

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

GNa

Conductance of fast sodium channel

GPCRs

G-protein-coupled receptors

Gto,f

Conductance of fast transient outward potassium current

Hz

Hertz

h

Hour

Ito,s

Slow component of transient outward potassium current

kcal

Kilocalorie

Kv

Voltage-gated potassium channel

KChIPs

Kv channel interacting proteins

ml

Milliliter

mRNA

Messenger ribonucleic acid

mS

Millisiemens

μF

Microfarad

Nav

Voltage-gated sodium channel

O2

Oxygen

OE

Overexpression

PAGE

Polyacrylamide gel electrophoresis

pH

Power of hydrogen

RER

Respiratory exchange ratio

SCN5A

Sodium channel, voltage-gated, type V alpha subunit

SD

Standard deviation

SDS

Sodium dodecyl sulfate

Tris-HCl

Tris–hydrochloride

Notes

Acknowledgments

We would like to acknowledge the technical assistance of Michael Migita in the performance of the study. The work was supported by Veteran Affairs Merit Awards from the Department of Veterans Affairs BX000783 (D. M. Roth), and BX001963 (H. H. Patel), National Institutes of Health HL105713 (R. C. Balijepalli), HL078878 (R. C. Balijepalli), HL091071 (H. H. Patel), HL107200 (H. H. Patel and D.M. Roth), HL066941 (H. H. Patel and D.M. Roth), HL115933 (H. H. Patel and D.M. Roth), GM103426 (A. D. McCulloch), HL105242 (A. D. McCulloch), and EB014593 (A. D. McCulloch). ADM is a co-founder, equity-holder, and scientific advisor to Insilicomed, Inc. This relationship is managed by a UCSD Conflict of Interest sub-committee. However, there was no involvement of Insilicomed, Inc. in the research described here. The authors have no additional financial disclosures.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Jan M. Schilling
    • 1
    • 2
  • Yousuke T. Horikawa
    • 3
    • 6
  • Alice E. Zemljic-Harpf
    • 1
    • 2
  • Kevin P. Vincent
    • 4
  • Leonid Tyan
    • 7
  • Judith K. Yu
    • 2
  • Andrew D. McCulloch
    • 4
    • 5
  • Ravi C. Balijepalli
    • 7
  • Hemal H. Patel
    • 1
    • 2
  • David M. Roth
    • 1
    • 2
  1. 1.Veterans Affairs San Diego Healthcare SystemSan DiegoUSA
  2. 2.Department of AnesthesiologyUniversity of California San DiegoLa JollaUSA
  3. 3.Department of PediatricsUniversity of California San DiegoLa JollaUSA
  4. 4.Department of BioengineeringUniversity of California San DiegoLa JollaUSA
  5. 5.Department of MedicineUniversity of California San DiegoLa JollaUSA
  6. 6.Department of PediatricsSharp Rees-Stealy Medical GroupSan DiegoUSA
  7. 7.Department of Medicine, Cellular and Molecular Arrhythmia Research ProgramUniversity of WisconsinMadisonUSA

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