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Electrophysiology and metabolism of caveolin-3-overexpressing mice

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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.

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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

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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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    Authors and Affiliations

    1. Veterans Affairs San Diego Healthcare System, San Diego, CA, USA

      Jan M. Schilling, Alice E. Zemljic-Harpf, Hemal H. Patel & David M. Roth

    2. Department of Anesthesiology, University of California San Diego, La Jolla, CA, USA

      Jan M. Schilling, Alice E. Zemljic-Harpf, Judith K. Yu, Hemal H. Patel & David M. Roth

    3. Department of Pediatrics, University of California San Diego, La Jolla, CA, USA

      Yousuke T. Horikawa

    4. Department of Bioengineering, University of California San Diego, La Jolla, CA, USA

      Kevin P. Vincent & Andrew D. McCulloch

    5. Department of Medicine, University of California San Diego, La Jolla, CA, USA

      Andrew D. McCulloch

    6. Department of Pediatrics, Sharp Rees-Stealy Medical Group, San Diego, CA, USA

      Yousuke T. Horikawa

    7. Department of Medicine, Cellular and Molecular Arrhythmia Research Program, University of Wisconsin, Madison, WI, USA

      Leonid Tyan & Ravi C. Balijepalli

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    J. M. Schilling and Y. T. Horikawa contributed as joint first authors.

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    Schilling, J.M., Horikawa, Y.T., Zemljic-Harpf, A.E. et al. Electrophysiology and metabolism of caveolin-3-overexpressing mice. Basic Res Cardiol 111, 28 (2016). https://doi.org/10.1007/s00395-016-0542-9

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    • DOI: https://doi.org/10.1007/s00395-016-0542-9

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