TY - JOUR
T1 - MCARD-mediated gene transfer of GRK2 inhibitor in ovine model of acute myocardial infarction
AU - Swain, Jabaris D.
AU - Fargnoli, Anthony S.
AU - Katz, Michael G.
AU - Tomasulo, Catherine E.
AU - Sumaroka, Marina
AU - Richardville, Kyle C.
AU - Koch, Walter J.
AU - Rabinowitz, Joseph E.
AU - Bridges, Charles R.
N1 - Funding Information:
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.
PY - 2013/4
Y1 - 2013/4
N2 - 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.
AB - 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.
KW - Acute myocardial infarction
KW - Gene therapy
KW - Molecular cardiac surgery
KW - β-Adrenergic receptors
UR - http://www.scopus.com/inward/record.url?scp=84882946336&partnerID=8YFLogxK
U2 - 10.1007/s12265-012-9418-z
DO - 10.1007/s12265-012-9418-z
M3 - Article
C2 - 23208013
AN - SCOPUS:84882946336
SN - 1937-5387
VL - 6
SP - 253
EP - 262
JO - Journal of Cardiovascular Translational Research
JF - Journal of Cardiovascular Translational Research
IS - 2
ER -