Aging in human subjects is associated with heightened susceptibility to injury triggered byischemia/reperfusion (I/R). Fundamental metabolic and biochemical changes occur in aging tissues in thebasal state, and consequent to I/R. Aged human and Fischer 344 rat hearts display increased accumulationof Advanced Glycation Endproducts (AGEs), the products of nonenzymatic glycation/oxidation ofproteins/lipids. AGEs may impart 'gain of function' in the tissues by virtue of their ability to trigger signalingpathways, via Receptor for AGE (RAGE). In human aging, in the absence of overt cardiovascular disease ordiabetes, increased expression/activity of the key polyol pathway enzyme aldose reductase (AR) occurs,leading to multiple metabolic disturbances, including generation of methylglyoxal (MG) and 3-deoxyglucosone (3-DG), precursors of AGEs. Aged human hearts, in the absence of cardiovasculardisease or risk factors, display increased expression of RAGE antigen vs. young hearts. Our preliminarydata reveal that myocardium of aged Fischer 344 rats (age, 24 mos), displays increased RAGE antigencompared to young rats (age, 4 months), particularly in endothelial cells (EC) and cardiomyocytes.Pharmacological blockade of RAGE in aged Fischer 344 rats attenuates I/R injury in the isolated perfusedheart. Thus, we hypothesize that in aging, accumulation of AGEs upregulates expression of RAGE, therebyestablishing basal dysfunction. Upon superimposed I/R, augmented ligand-RAGE mechanisms set the stagefor enhanced biochemical and inflammatory stress and impairment in metabolism. Together, these forcesconverge to magnify I/R injury. We will test these concepts in aged Fischer 344 rats and RAGE mutantmice. These studies will be built on the premise that pharmacological blockade of RAGE may represent apotent strategy for the prevention of age-related cardiovascular dysfunction. Project 2 is closely linked toProjects 1&3, as each studies aging-linked enhanced vulnerability to I/R in the intact heart and isolated ECand cardiomyocytes, respectively. Project 2 shares mouse/rat models with Projects 1 and 3. Project 2 willutilize all three Cores of the Program Project during all five years of the grant.
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