Intracoronary, adenovirus-mediated Akt gene transfer in heart limits infarct size following ischemia-reperfusion injury in vivo

Background: Previous data have shown that enhanced Akt signaling inhibits c ardiac myocyte apoptosis in vitro and in vivo. To elucidate the contributio n of apoptosis to the pathogenesis of the infarct, we investigated whether intra-coronary Akt gene delivery could reduce gross infarct size following ischemia/ reperfusion injury. Methods and Results: Replication-defective ad enoviral constructs encoding a myristoylated, constitutively-active form of Akt (myrAkt) or beta -galactosidase were delivered to rat hearts by intrac oronary perfusion. Twenty-four h after gene transduction, hearts in both gr oups underwent 45 min of ischemia followed by 4 h of reperfusion. A third g roup of animals also underwent ischemia-reperfusion injury but were not tra nsduced with an adenoviral vector, The proportion of the left ventricle at risk was not different among the experimental groups. However, infarct size as a proportion of the area at risk was significantly lower in myrAkt-trea ted group than in the beta -galactosidase treated group or in the control g roup that was not subject to intracoronary perfusion (myrAkt = 20.9+/-2.7% v beta -galactosidase = 56.1+/-3.9% and control = 46.2+/-4.6%, P<0.05), as was infarct size as a proportion of the total left ventricle (myrAkt = 11.4 +/-3.2 v <beta>-galactosidase = 32.9+/-3.3 and control = 23.5+/-3.0, P<0.05 ). Conclusions: These data demonstrate that Akt signaling limits infarct si ze following ischemia/reperfusion injury and they indicate that the activat ion of this pathway may be useful in protecting against myocardial loss in the diseased heart. (C) 2000 Academic Press.