Abstract 5139: Critical Role of CalDAG-GEFI Signaling in Myocardial Ischemia-Reperfusion Injury
Background: Myocardial infarction (MI) is a national health concern, with an occurrence of over 1 million cases per year. An event central to MI is reperfusion injury, i.e. the damage to tissue caused when blood supply returns to the tissue after the period of ischemia. An important role for both leukocytes and platelets in the development of reperfusion injury has been described. Our recent studies demonstrated that the signaling molecule CalDAG-GEFI (Calcium and diacyglycerol-regulated guanine nucleotide exchange factor I) is predominantly expressed in neutrophils and platelets, where it plays a critical role for integrin activation and cell adhesion. Objective: We evaluated if CalDAG-GEFI is a potential target for intervention with reperfusion injury.
Methods/Results: Myocardial ischemia was induced for 30 minutes in wild-type (WT) and CalDAG-GEFI−/− mice by a minimally invasive operative procedure. After 24 hours of reperfusion, the mice were sacrificed and the hearts were extracted for further analysis. CalDAG-GEFI-deficient mice showed an approximately 40% reduction in infarct size compared to WT mice (48% vs. 30% in WT and CalDAG-GEFI−/− respectively). In order to rule out that CalDAG-GEFI affects mI/R injury due to its role in endothelial cell and/or cardiomyocyte function, we first studied its expression in these cell types. Compared to the strong expression in both platelets and neutrophils, only trace amounts of CalDAG-GEFI expression were observed in cardiomyocytes or endothelial cells. In a next step, mI/R injury was studied in lethally irradiated CalDAG-GEFI−/− mice reconstituted with bone marrow isolated from WT (KO/WT) or CalDAG-GEFI−/− (KO/KO) mice. As expected, the infarct size in KO/WT chimeras was similar to that observed in WT mice and significantly larger than that of KO/KO chimeras, strongly suggesting that CalDAG-GEFI is critical for the development of mI/R injury due to its role in platelet and/or neutrophil function. Interestingly, CalDAG-GEFI−/− mice showed a stronger protection from mI/R injury than neutrophil-depleted WT mice.
Conclusion: Our studies identify CalDAG-GEFI as a novel and promising intracellular therapeutic target for the reduction of myocardial reperfusion injury.