Effects of Akt activation in ischemia-reperfusion injury

Massachusetts General Hospital, Boston MA

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Abstract

Cardiomyocyte apoptosis has been identified in many clinically important cardiac conditions including heart failure and ischemia- reperfusion injury. During the last project period, the overall goal was to understand the role of specific IGF-I receptor-mediated signaling pathways in blocking cardiomyocyte apoptosis and define the func- tional contribution of these pathways in an acute model of ischemia- reperfusion injury (IRI). We found that the serine-threonine kinase, Akt, is a critical mediator of IGF-I-induced survival signaling in cardiomyocytes in acute models of transient ischemia both in vitro and in vivo. However, the long-term effects of Akt activation, as well as the downstream mechanisms involved, are currently unknown. The goals of the current proposal are to define the long-term effects of acute and chronic Akt activation in models of IRI, as well as to identify the downstream mechanisms that mediate these effects. This proposal is based on three hypotheses: 1) that acute and chronic Akt activation mediates significant functional and anatomic benefits in IRI that are sustained over time, 2) that the benefits of Akt activation in IRI result from its ability to simultaneously improve cardiomyocyte survival and function and that 3) these benefits are mediated via distinct downstream signaling mechanisms. To test these hypotheses, cardiac expression of mutant and wild-type Akt constructs will be achieved through somatic and germline gene transfer, to define the effects of Akt activation and identify potential downstream mediators. In Specific Aim 1, we will define the downstream mechanisms responsible for the benefits of Akt activation on cardiomyocyte survival and function in vitro and in vivo. In Specific Aim 2, we will examine the long-term effects of transient Akt activation in rat models of IRI and infarction. In Specific Aim 3, we will evaluate the effects of chronic cardiac Akt activation at baseline and in models of IRI and infarction. Understanding the role of specific signaling pathways in cardiomyocyte survival and function may provide novel therapeutic approaches for the management of many clinically important cardiac disorders.