Acute ischemic cardiac dysfunction is attenuated via gene transfer of a peptide inhibitor of the β-adrenergic receptor kinase (βARK1)

• Published in: The journal of gene medicine 2005-09, Vol.7 (9), p.1172-1177
• Main Authors: Tevaearai, Hendrik T., Brant Walton, G., Keys, Janelle R., Koch, Walter J., Eckhart, Andrea D.
• Format: Article
• Language: English
• Subjects: Adenoviridae; Animals; beta-Adrenergic Receptor Kinases; Coronary Artery Bypass, Off-Pump; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - metabolism; Disease Models, Animal; gene therapy; Genetic Therapy - methods; Genetic Vectors; Heart Ventricles - metabolism; myocardial ischemia; Myocardial Ischemia - drug therapy; Myocardial Ischemia - physiopathology; off-pump coronary artery bypass graft; Peptides - genetics; Peptides - metabolism; Peptides - therapeutic use; Postoperative Complications - prevention & control; Premedication; Rabbits; Receptors, Adrenergic, beta; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Recombinant Proteins - therapeutic use; Transgenes; Ventricular Dysfunction, Left - prevention & control; Ventricular Function, Left; β-adrenergic receptor; β-adrenergic receptor kinase
• ISSN: 1099-498X; 1521-2254
• DOI: 10.1002/jgm.770

Acute myocardial ischemia is a critical adverse effect potentially occurring during cardiac procedures. A peptide inhibitor of the β‐adrenergic receptor kinase (βARK1), βARKct, has been successful in rescuing chronic myocardial ischemia. The present study focused on the effects of adenoviral‐mediated βARKct (Adv‐βARKct) delivery on left ventricle (LV) dysfunction induced by acute coronary occlusion. Rabbits received intracoronary delivery of phosphate‐buffered saline (PBS) (n = 9) or 5 × 1011 viral particles of βARKct (n = 8). A loose prolene 5‐0 Potz‐loop suture was placed around the circumflex coronary artery (LCx) with both ends buried under the skin. Four days later, the suture was retrieved and pulled to occlude the LCx. Ischemia was confirmed by immediate ECG changes. LV function was continuously recorded for 45 min. Contractility (LVdP/dtmax), relaxation (LVdP/dtmin) and end diastolic pressure (EDP) were less impaired in the βARKct group as compared to PBS (P < 0.05, two‐way ANOVA). βAR density was higher in the ischemic area of the LV in the βARKct group (βARKct: 71.9 ± 4.6 fmol/mg protein, PBS: 54.5 ± 4.0 fmol/mg protein, P < 0.05). Adenylyl cyclase activity was also improved basally and in response to βAR stimulation. βARK1 activation was less in the βARKct group (P < 0.05). Therefore, inhibition of myocardial βARK1 may represent a new strategy to prevent LV dysfunction induced by acute coronary ischemia. Copyright © 2005 John Wiley & Sons, Ltd.