Overwhelming evidence suggest that mitochondria plays a causative role in diabetic endothelial dysfunction. How mitochondria become dysfunctional remains enigmatic. Our exciting preliminary data indicate that diabetes instigates aberrant mitochondrial fission by suppressing autophagy-dependent degradation of the dynamin-related protein 1 (DRP1), a molecule essential for mitochondrial fission. The central hypothesis of this application that selective impairment autophagy-mediated DRP1 degradation in diabetes instigates vascular endothelial dysfunction and accelerates atherosclerosis. This hypothesis will be tested using gain-/loss-of-function strategies in both animal models and cultured cells.
Aim 1 is to test the hypothesis that defective vascular autophagy increases mitochondrial fission in the development of endothelial dysfunction and atherosclerosis by characterizing the spatial and temporal dynamics of vascular autophagy, mitochondrial fission, and endothelial dysfunction in Akita mice (type 1 diabetes) and ob/ob mice (type 2 diabetes), determining whether inhibition of autophagy aggravates mitochondrial fission, endothelial dysfunction, and atherosclerosis in diabetic LDLr-/-/beclin1 heterozygous (beclin1+/-, with reduced autophagy) mice and their littermates, and examining whether enhanced endothelial autophagy lessens oxidative stress and improves endothelial function in diabetic Atg7 endothelium-specific transgenic mice (with enhanced autophagy).
Aim 2 is to delineate the mechanisms by which diabetes-inhibited autophagy increases mitochondrial fission.
This aim will test the hypothesis that diabetes induces mitochondrial fission by inhibiting autophagic degradation of DRP1. Proposed studies are significant as the completion of this proposal will provide the rationales for developing new therapeutics to prevent/treat cardiovascular complications in diabetes.
Proposed studies aims to dissect how high glucose promotes mitochondrial dysfunction and how mitochondrial fission results in to endothelial dysfunction and atherosclerosis. We expect the completion of this proposal will provide the rationales for developing new therapeutics to prevent/treat cardiovascular complications in diabetes.
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