Aging in human subjects is accompanied by the inevitable development of cardiovascular and endothelialdysfunction, which, over time, especially as co-incident and superimposed aging-related disorders mount,leads to a heightened vulnerability to ischemia/reperfusion (I/R) stress. In response to the critique, we havedeveloped and focused this project on two key components of aging cardiovasculature that prime the agedorganism for amplified injury, both innately, and upon I/R. These studies are tightly coupled to Projects 1 & 2of this Program. First, basal degrees of inflammation increase in aged vasculature, particularly in agedendothelial cells (EC). Second, innate cardiomyocyte dysfunction develops in aging. Mitochondria becomedefective in cardiomyocytes as they age and increase generation of reactive oxygen species (ROS), therebyimpairing ATP generation. Such fundamental injury phenomena promote conditions for enhanced cell death- especially in I/R. Thus, in both EC and cardiomyocytes retrieved from aged animals, identification of theprecise signal transduction and transcriptional regulation mechanisms underlying these findings is essentialin identifying novel targets to suppress adverse cardiovascular aging and diminish the amplified vulnerabilityto I/R stress. We will probe the hypothesis that increased activity of the polyol enzyme AR in aging drivesmechanisms that enhance generation of AGE, thereby recruiting RAGE and consequent signal transductionin EC and cardiomyocytes; mechanisms which we predict are linked to cardiovascular dysfunction. Wepropose that when aged organisms are exposed to superimposed I/R stress in the heart, increased AR andAGE-RAGE signaling amplify production of inflammatory and stress mediators that exaggerate injury in theaged heart. In a manner highly synergistic with Projects 1&2 (intact heart), isolated EC and cardiomyocytesfrom aged animals will be used to probe the signal transduction and transcription factor mechanisms thatregulate basal and I/R stress in the aged heart. Project 3 shares mouse/rat models with Projects 1 and 2.Project 3 will utilize all three Cores of the Program Project during all five years of the grant.
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