The PIs of this application have developed techniques for producing and studying atherosclerosis using funds from the first AMDCC program. Specifically, we have found that streptozotocin-treated mice develop increased atherosclerosis in the presence of a transgene for human aldose reductase (hAR). We have also noted that hearts from these mice have areas of cardiac apoptosis. In addition, we have developed novel methods to study atherosclerosis regression that can be applied to studies of lesions in control and diabetic mice.
Aim 1 To create new mouse models of diabetic cardiovascular disease: We propose to create two new genetically altered mice.
Aim 1 a is to use the tet on system to allow expression of hAR in a time dependent manner. This system will allow us to test whether hAR expression in established lesions alters plaque morphology. These animals can also be used to produce tissue specific expression of hAR.
Aim 1 b is to produce mice with expression of hAR in cardiomyocytes. These mice, we hypothesize, will develop cardiomyopathy with diabetes.
Aim 2 To study the development of vascular lesions in diabetic mice: Mild diabetes due to deficiency of Pdx1 or high fat diets did not alter atherosclerosis in Ldlr-/- mice. In addition, Pdx1 did not affect regression after transplant of arteries containing atherosclerosis. We will use two additional methods to generate hyperglycemia, Akita and high fat diets on the FVB background, in Ldlr-/- mice ? hAR. Increased vascular disease in STZ-treated hAR mice could result from greater monocyte/macrophage accumulation in lesions, or could be secondary to a defect in lesion regression. Both processes will be studied in vivo and mechanistic information obtained by studying gene and protein expression.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZDK1-GRB-4 (M1))
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Liu, Lijuan
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Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Yuan, Chujun; Hu, Jiyuan; Parathath, Saj et al. (2018) Human Aldose Reductase Expression Prevents Atherosclerosis Regression in Diabetic Mice. Diabetes 67:1880-1891
Willecke, Florian; Scerbo, Diego; Nagareddy, Prabhakara et al. (2015) Lipolysis, and not hepatic lipogenesis, is the primary modulator of triglyceride levels in streptozotocin-induced diabetic mice. Arterioscler Thromb Vasc Biol 35:102-10
Willecke, Florian; Yuan, Chujun; Oka, Kazuhiro et al. (2015) Effects of High Fat Feeding and Diabetes on Regression of Atherosclerosis Induced by Low-Density Lipoprotein Receptor Gene Therapy in LDL Receptor-Deficient Mice. PLoS One 10:e0128996
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Nagareddy, Prabhakara R; Murphy, Andrew J; Stirzaker, Roslynn A et al. (2013) Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab 17:695-708
Son, Ni-Huiping; Ananthakrishnan, Radha; Yu, Shuiqing et al. (2012) Cardiomyocyte aldose reductase causes heart failure and impairs recovery from ischemia. PLoS One 7:e46549
Vedantham, Srinivasan; Noh, HyeLim; Ananthakrishnan, Radha et al. (2011) Human aldose reductase expression accelerates atherosclerosis in diabetic apolipoprotein E-/- mice. Arterioscler Thromb Vasc Biol 31:1805-13
Ramasamy, Ravichandran; Goldberg, Ira J (2010) Aldose reductase and cardiovascular diseases, creating human-like diabetic complications in an experimental model. Circ Res 106:1449-58
Noh, Hye-Lim; Hu, Yunying; Park, Tae-Sik et al. (2009) Regulation of plasma fructose and mortality in mice by the aldose reductase inhibitor lidorestat. J Pharmacol Exp Ther 328:496-503
Goldberg, Ira J; Hu, Yunying; Noh, Hye-Lim et al. (2008) Decreased lipoprotein clearance is responsible for increased cholesterol in LDL receptor knockout mice with streptozotocin-induced diabetes. Diabetes 57:1674-82

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