VEGF sub(165) transfection decreases postischemic NF- Kappa B-dependent myocardial reperfusion injury in vivo: role of eNOS phosphorylation

Recent advances in understanding the signal transduction of VEGF revealed a specific phosphorylation pathway of receptor-dependent PI3-kinase, AKT, and eNOS phosphorylation. Earlier studies have shown a role of this pathway in the mediation of angiogenic functions of VEGF such as an increase in capillary density in chronic ischemic in vivo models. Considering application of long-acting vectors transducing cardiac cells with VEGF constructs, however, the role of VEGF during short-term ischemia and reperfusion is a compelling problem, since these episodes tend to occur in coronary no-option patients. Applying liposomal transfection into coronary endothelial cells or the ischemic area of a pig heart, we investigated the role of regional myocardial VEGF transfection in the context of postischemic inflammation by investigating its effect on 1) postischemic NF- Kappa B activation and 2) subsequent leukocyte recruitment, which is closely associated with 3) subsequent infarct development and 4) loss of regional myocardial function. All results were compared with those obtained by additional NOS inhibition (L-NAME) or by transfection of a phosphomimetic eNOS construct (eNOS S1177D).