? While diabetes mellitus can lead to serious damage to many organs, cardiovascular diseases are the major cause of death and morbidity in diabetic patients. Overall, patients with diabetes have a three to five fold increased risk of coronary artery diseases compared to non-diabetics. Our goal is to use mouse genetics for identifying genetic risk factors for the vascular complications of diabetes and for unraveling underlying mechanisms. Although a significant increase in atherosclerosis by diabetes has been demonstrated in atherogenic mouse models, none of these mouse models faithfully replicates the types of dyslipidemia associated with diabetes in humans. We postulate that this failure is due to differences in the relative levels of plasma low density lipoprotein (LDL) and plasma high density lipoprotein (HDL) that are controlled by genetic differences between the two species and genetic polymorphisms in humans. Thus our first hypothesis is that humanizing genes that are involved in lipoprotein metabolism in mice so that they develop a more human-like diabetic dyslipidemia will cause them to replicate better the cardiovascular problems of human diabetic patients. We will test this hypothesis in Specific Aim 1 by inducing diabetes in mice with humanized apoE of the three isoforms (E2, E3, and E4) and humanized LDL receptor (LDLR), with or without overexpression of human apoB. We predict that this will lead to diabetic dyslipidemia and accelerated atherosclerosis in an apoE isoform dependent manner. Our second hypothesis is that since diabetes is generally acknowledged to induce oxidative stress, genetically determined differences in the levels of endogenous anti-oxidants affect the development of cardiovascular complications,. To test this hypothesis, we propose in Specific Aim 2 to develop a new mouse model with a genetically controlled reduction in the production of the endogenous antioxidant lipoic acid (LA). We will modify the LA synthase (Lias) gene in such a way that the stability of Lias mRNA will be drastically reduced in a tissue specific fashion. Our hypothesis predicts that reduced production of LA will increase the oxidative stress already present in diabetic mice and enhance their development of vascular complications.
In Specific Aim 3, we propose to combine human-like diabetic dyslipidemia with genetically reduced antioxidant capacity due to LA deficiency to test our overall thesis that interactions between genetic polymorphic differences affecting lipid profiles and genetic differences affecting endogenous antioxidant levels determine the degree to which diabetes enhances cardiovascular disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01HL087946-01
Application #
7148777
Study Section
Special Emphasis Panel (ZDK1-GRB-4 (M1))
Program Officer
Rabadan-Diehl, Cristina
Project Start
2006-09-04
Project End
2011-08-31
Budget Start
2006-09-04
Budget End
2007-08-31
Support Year
1
Fiscal Year
2006
Total Cost
$361,799
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Hiller, Sylvia; DeKroon, Robert; Hamlett, Eric D et al. (2016) Alpha-lipoic acid supplementation protects enzymes from damage by nitrosative and oxidative stress. Biochim Biophys Acta 1860:36-45
Xu, Longquan; Hiller, Sylvia; Simington, Stephen et al. (2016) Influence of Different Levels of Lipoic Acid Synthase Gene Expression on Diabetic Nephropathy. PLoS One 11:e0163208
Hiller, Sylvia; DeKroon, Robert; Xu, Longquan et al. (2014) ?-Lipoic acid protects mitochondrial enzymes and attenuates lipopolysaccharide-induced hypothermia in mice. Free Radic Biol Med 71:362-7
James, Leighton R; Le, Catherine; Doherty, Heather et al. (2013) Connective tissue growth factor (CTGF) expression modulates response to high glucose. PLoS One 8:e70441
Johnson, Lance A; Kim, Hyung-Suk; Knudson, Melissa J et al. (2013) Diabetic atherosclerosis in APOE*4 mice: synergy between lipoprotein metabolism and vascular inflammation. J Lipid Res 54:386-96
Fox, Raymond G; Magness, Scott; Kujoth, Gregory C et al. (2012) Mitochondrial DNA polymerase editing mutation, PolgD257A, disturbs stem-progenitor cell cycling in the small intestine and restricts excess fat absorption. Am J Physiol Gastrointest Liver Physiol 302:G914-24
Pendse, Avani A; Johnson, Lance A; Kim, Hyung-Suk et al. (2012) Pro- and antiatherogenic effects of a dominant-negative P465L mutation of peroxisome proliferator-activated receptor-? in apolipoprotein E-Null mice. Arterioscler Thromb Vasc Biol 32:1436-44
Yi, Xianwen; Xu, Longquan; Hiller, Sylvia et al. (2012) Reduced expression of lipoic acid synthase accelerates diabetic nephropathy. J Am Soc Nephrol 23:103-11
Yi, Xianwen; Xu, Longquan; Hiller, Sylvia et al. (2012) Reduced alpha-lipoic acid synthase gene expression exacerbates atherosclerosis in diabetic apolipoprotein E-deficient mice. Atherosclerosis 223:137-43
Johnson, Lance A; Arbones-Mainar, Jose M; Fox, Raymond G et al. (2011) Apolipoprotein E4 exaggerates diabetic dyslipidemia and atherosclerosis in mice lacking the LDL receptor. Diabetes 60:2285-94

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