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MCARD-Mediated Gene Transfer of GRK2 Inhibitor in Ovine Model of Acute Myocardial Infarction

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Abstract

β-Adrenergic receptor (βAR) dysfunction in acute myocardial infarction (MI) is associated with elevated levels of the G-protein-coupled receptor kinase-2 (GRK2), which plays a key role in heart failure progression. Inhibition of GRK2 via expression of a peptide βARKct transferred by molecular cardiac surgery with recirculating delivery (MCARD) may be a promising intervention. Five sheep underwent scAAV6-mediated MCARD delivery of βARKct, and five received no treatment (control). After a 3-week period, the branch of the circumflex artery (OM1) was ligated. Quantitative PCR data showed intense βARKct expression in the left ventricle (LV). Circumferential fractional shortening was 23.4 ± 7.1 % (baseline) vs. −2.9 ± 5.2 % (p < 0.05) in the control at 10 weeks. In the MCARD-βARKct group, this parameter was close to baseline. The same trend was observed with LV wall thickening. Cardiac index fully recovered in the MCARD-βARKct group. LV end-diastolic volume and LV end-diastolic pressure did not differ in both groups. MCARD-mediated βARKct gene expression results in preservation of regional and global systolic function after acute MI without arresting progressive ventricular remodeling.

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Abbreviations

βAR:

β-Adrenergic receptor

MI:

Myocardial infarction

GRK2:

G-protein-coupled receptor kinase-2

βARKct:

Carboxyl-terminal portion of GRK2

MCARD:

Molecular cardiac surgery with recirculating delivery

MRI:

Magnetic resonance imaging

RTqPCR:

Reverse Transcriptase real-time quantitative polymerase chain reaction

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Acknowledgments

This work was sponsored in part by the National Heart, Lung, and Blood Institute (1-R01-HL083078-01A2) and the Gene Therapy Resource Program (GTRP) of the National Heart, Lung, and Blood Institute NIH P30-DKO47757. We would like to extend acknowledgments to Charles Yarnall, Alice Isidro, and Michael Petrov for their excellent technical assistance. We also thank Ted Plappert for completing echocardiography studies and James Pilla for MRI studies as well as Natalia Zinchenko and Jane Ingram for performing histological staining. Anthony Carty, JanLee Jensen, James Marx, Jennifer Kirsch, and Allison Czarnecki deserve thanks as well for excellent care and handling of the animals in the Biomedical Research Building and Glenolden Vivarium-University of Pennsylvania.

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Authors and Affiliations

  1. Department of Surgery, Division of Cardiovascular Surgery, University of Pennsylvania Medical Center, Philadelphia, PA, USA

    JaBaris D. Swain, Catherine E. Tomasulo & Marina Sumaroka

  2. Temple University School of Medicine, Philadelphia, PA, USA

    Walter J. Koch & Joseph E. Rabinowitz

  3. Sanger Heart and Vascular Institute, Cannon Research Center, Carolinas HealthCare System, 1001 Blythe Blvd, Suite 300, Charlotte, NC, 28203, USA

    Anthony S. Fargnoli, Michael G. Katz, Kyle C. Richardville & Charles R. Bridges

Authors
  1. JaBaris D. Swain
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  2. Anthony S. Fargnoli
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  3. Michael G. Katz
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  4. Catherine E. Tomasulo
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  5. Marina Sumaroka
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  6. Kyle C. Richardville
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  7. Walter J. Koch
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  8. Joseph E. Rabinowitz
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  9. Charles R. Bridges
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Corresponding author

Correspondence to Charles R. Bridges.

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J. D. Swain, A. S. Fargnoli and M. G. Katz contributed equally to this article.

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Swain, J.D., Fargnoli, A.S., Katz, M.G. et al. MCARD-Mediated Gene Transfer of GRK2 Inhibitor in Ovine Model of Acute Myocardial Infarction. J. of Cardiovasc. Trans. Res. 6, 253–262 (2013). https://doi.org/10.1007/s12265-012-9418-z

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  • DOI: https://doi.org/10.1007/s12265-012-9418-z

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