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Cardiac Electrical Activity in a Genomically “Humanized” Chromogranin A Monogenic Mouse Model with Hyperadrenergic Hypertension

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Abstract

The prohormone chromogranin A (CHGA) is ubiquitously found in vesicles of adrenal chromaffin cells and adrenergic neurons, and it is processed to the hypotensive hormone peptide catestatin (CST). Both CHGA and CST regulate blood pressure and cardiac function. This study addresses their role in cardiac electrical activity. We have generated two genomically “humanized” transgenic mouse strains (Tg31CHGA+/+; Chga−/− (HumCHGA31) and Tg19CHGA+/+; Chga−/− (HumCHGA19)) with varied CHGA expression and the ability to rescue the Chga−/− phenotype (hypertensive, hyperadrenergic with dilated cardiomyopathy). The normotensive HumCHGA31 mice express CHGA at levels comparable to wild-type. In contrast, the hypertensive HumCHGA19 mice have low levels of CHGA. EKG recordings revealed that the QT interval, R-amplitude, and QRS time-voltage integral are markedly longer in HumCHGA19 compared to wild-type and HumCHGA31 mice. These differences are accompanied by increased heart rate and QT variability, indicating that ventricular assault happens in a status of low levels of circulating CST.

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Abbreviations

au:

Arbitrary unit

BP:

Blood pressure

Chga :

Mouse chromogranin A gene

CHGA :

Human chromogranin A gene

CHGA:

Chromogranin A protein

CI:

Statistical confidence interval

CST:

Catestatin

cv:

Coefficient of variation = [standard deviation/sample mean]

DBP:

Diastolic BP

DCM:

Dilated cardiomyopathy

EKG:

Electrocardiography

HR:

Heart rate

HumCHGA19:

Genomically “humanized” transgenic mice Tg19CHGA+/+Chga−/−

HumCHGA31:

Genomically “humanized” transgenic mice Tg31CHGA+/+Chga−/−

HRV:

Heart rate variability

PQ:

Atrio-ventricular conduction time

QRSd:

Duration of QRS-wave complex

QTb:

Bazett-corrected QT interval

QTb/PQ:

Cardiomyopathy index

QTu:

Uncorrected QT interval

QTVI:

QT variability index

RR:

Sinus cycle length

SBP:

Systolic BP

WT:

Wild-type mice

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Acknowledgments

This study was supported by grants from the National Institutes of Health—K01DK069613 and R01 HL108629 to Vaingankar, S.M. We would like to thank Professors O’Connor, D. T., Pajor A., Mahata, S. K., and Ahmad, H.R. for their critical input.

Disclosures

The authors declare no conflicts of interest.

Author information

Authors and Affiliations

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

    Nagendu B. Dev, Saiful A. Mir, Jawed A. Siddiqui, Maja Mustapic & Sucheta M. Vaingankar

  2. CSIR-Central Drug Research Institute, Lucknow, India

    Jiaur R. Gayen

Authors
  1. Nagendu B. Dev
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  2. Saiful A. Mir
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  3. Jiaur R. Gayen
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  4. Jawed A. Siddiqui
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  6. Sucheta M. Vaingankar
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Corresponding author

Correspondence to Sucheta M. Vaingankar.

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Editor-in-Chief Jennifer L. Hall oversaw the review of this article

Nagendu B. Dev and Saiful A. Mir contributed equally to this work.

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Dev, N.B., Mir, S.A., Gayen, J.R. et al. Cardiac Electrical Activity in a Genomically “Humanized” Chromogranin A Monogenic Mouse Model with Hyperadrenergic Hypertension. J. of Cardiovasc. Trans. Res. 7, 483–493 (2014). https://doi.org/10.1007/s12265-014-9563-7

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  • DOI: https://doi.org/10.1007/s12265-014-9563-7

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