title: MCARD-mediated gene transfer of GRK2 inhibitor in ovine model of acute myocardial infarction.
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.
authors.affiliation: Department of Surgery, Division of Cardiovascular Surgery, University of Pennsylvania Medical Center, Philadelphia, PA, USA.
authors.forename: JaBaris D
authors.initials: JD
authors.lastname: Swain
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Fargnoli
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katz
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Tomasulo
authors.forename: Marina
authors.initials: M
authors.lastname: Sumaroka
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Richardville
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Rabinowitz
authors.forename: Charles R
authors.initials: CR
authors.lastname: Bridges
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D008279:Magnetic Resonance Imaging; D008297:Male; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D020127:Recovery of Function; D012756:Sheep; D013318:Stroke Volume; D013599:Systole; D013997:Time Factors; D016277:Ventricular Function, Left; D017725:Ventricular Pressure; D020257:Ventricular Remodeling
chemical_list: D010446:Peptide Fragments; D011943:Receptors, Adrenergic, beta; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2