Acute ischemic cardiac dysfunction is attenuated via gene transfer of a peptide inhibitor of the beta-adrenergic receptor kinase (betaARK1).
Acute myocardial ischemia is a critical adverse effect potentially occurring during cardiac procedures. A peptide inhibitor of the beta-adrenergic receptor kinase (betaARK1), betaARKct, has been successful in rescuing chronic myocardial ischemia. The present study focused on the effects of adenoviral-mediated betaARKct (Adv-betaARKct) delivery on left ventricle (LV) dysfunction induced by acute coronary occlusion. Rabbits received intracoronary delivery of phosphate-buffered saline (PBS) (n=9) or 5x10(11) viral particles of betaARKct (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 betaARKct group as compared to PBS (P<0.05, two-way ANOVA). betaAR density was higher in the ischemic area of the LV in the betaARKct group (betaARKct: 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 betaAR stimulation. betaARK1 activation was less in the betaARKct group (P<0.05). Therefore, inhibition of myocardial betaARK1 may represent a new strategy to prevent LV dysfunction induced by acute coronary ischemia.
Tevaearai
Hendrik T
HT
Department of Cardiovascular Surgery, University Hospital, Bern, Switzerland.
Walton
G Brant
GB
Keys
Janelle R
JR
Koch
Walter J
WJ
Eckhart
Andrea D
AD
D000256:Adenoviridae; D000818:Animals; D047549:Coronary Artery Bypass, Off-Pump; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006352:Heart Ventricles / Q000378:metabolism; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D011183:Postoperative Complications / Q000517:prevention & control; D011292:Premedication; D011817:Rabbits; D011943:Receptors, Adrenergic, beta; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D019076:Transgenes; D018487:Ventricular Dysfunction, Left / Q000517:prevention & control*; D016277:Ventricular Function, Left; D051552:beta-Adrenergic Receptor Kinases
D010455:Peptides; D011943:Receptors, Adrenergic, beta; D011994:Recombinant Proteins; C445259:beta-adrenergic receptor kinase inhibitory peptide; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases