This proposal is submitted to become a pathobiology site in the renewal of the Animal Models of Diabetic Complications Consortium (AMDCC). The University of Utah site proposes to generate two mouse models. The first will address mechanisms that are responsible for diabetic cardiomyopathy, and the second will model the role of impaired angiogenesis and arteriogenesis in the pathogenesis of ischemic complications of diabetes. Our studies in the first phase of the consortium revealed that diabetic cardiomyopathy (particularly in type 2 diabetes) was characterized by impaired myocardial insulin action, mitochondria! dysfunction, oxidative stress, increased FA utilization, decreased glucose utilization and lipotoxicity. Mice with cardiomyocyte-restricted deletion of insulin receptors (CIRKO), developed many of the features of diabetic cardiomyopathy but did not have a persistent increase in FA oxidation, did not develop lipotoxicity and had modest defects in cardiac function. We therefore propose to introduce into CIRKO mice an Acyl-CoA synthetase transgene that will modestly increased myocardial FA delivery in a sensitized background of mitochondrial superoxide (Sod2) haploinsufficency. We will then determine if these mice meet established AMDCC criteria for diabetic cardiomyopathy, determine if they exhibit characteristic defects in mitochondrial function and substrate utilization and test the hypothesis that they will be more susceptible to dysfunction in the face of LV hypertrophy.This model represents a powerful platform with which to test the direct effect of various therapeutic strategies on diabetic cardiomyopathy, independently of effects on systemic metabolism. We will also generate a mouse in the type -1 diabetes (Akita) background with temporal and cell-type restricted expression of a novel angiogenic factor netrin 1. We will use this mouse to determine if the maintenance of arteriogenesis and angiogenesis, by activating this transgene in the heart or the hind-limb will be sufficient to ameliorate the accelerated LV remodeling that characterizes diabetic hearts following coronary artery ligation, or reverse impaired recovery of hind-limb perfusion that occurs in diabetic animals following femoral artery occlusion. This model will also be a powerful platform with which to evaluate the role of impaired angiogenesis (in the pathogenesis), or therapeutic angiogenesis (in the treatment) of other ischemic complications of diabetes such as impaired wound healing, neuropathy or nephropathy.
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