Creating Glucose Responsive Cardiovascular Complications
Principal Investigator: IRA JAY GOLDBERG
Affiliation: Columbia University
Abstract: 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 1a 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 1b 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.
Funding Period: 2006-09-04 - 2011-07-31
more information: NIH RePORT
- Cardiomyocyte aldose reductase causes heart failure and impairs recovery from ischemiaNi Huiping Son
Department of Medicine, Columbia University Medical Center, New York, New York, United States of America
PLoS ONE 7:e46549. 2012..These results suggest that pharmacological inhibition of AR will be beneficial during ischemia and in some forms of heart failure...
- Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosisPrabhakara R Nagareddy
Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, New York, NY 10032, USA
Cell Metab 17:695-708. 2013..In patients with type 1 diabetes, plasma S100A8/S100A9 levels correlate with leukocyte counts and coronary artery disease. Thus, hyperglycemia drives myelopoiesis and promotes atherogenesis in diabetes...
- Adipose tissue macrophages promote myelopoiesis and monocytosis in obesityPrabhakara R Nagareddy
Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, New York, NY 10032, USA Department of Internal Medicine, University of Kentucky, Lexington, KY 40514, USA
Cell Metab 19:821-35. 2014..These studies uncover a positive feedback loop between ATMs and BM myeloid progenitors and suggest that inhibition of TLR4 ligands or the NLRP3-IL-1β signaling axis could reduce AT inflammation and insulin resistance in obesity. ..
- Aldose reductase and cardiovascular diseases, creating human-like diabetic complications in an experimental modelRavichandran Ramasamy
Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
Circ Res 106:1449-58. 2010..For AR, this will require tissue specific expression of AR in sites and at levels that approximate those in humans...
- Human aldose reductase expression accelerates atherosclerosis in diabetic apolipoprotein E-/- miceSrinivasan Vedantham
Division of Endocrinology, New York University Langone Medical Center, NY 10016, USA
Arterioscler Thromb Vasc Biol 31:1805-13. 2011..The polyol pathway mediated by aldose reductase (AR) has been postulated to be one such pathway. However, it has been reported that AR reduces toxic lipid aldehydes and, under some circumstances, might be antiatherogenic...
- Recipes for creating animal models of diabetic cardiovascular diseaseWilla Hsueh
Division of Endocrinology, Diabetes, and Hypertension, The David Geffen School of Medicine, University of California, Los Angeles, CA, USA
Circ Res 100:1415-27. 2007....
- Decreased lipoprotein clearance is responsible for increased cholesterol in LDL receptor knockout mice with streptozotocin-induced diabetesIra J Goldberg
Division of Preventive Medicine, Columbia University, New York, New York 10032, USA
Diabetes 57:1674-82. 2008..Patients with diabetes often have dyslipidemia and increased postprandial lipidmia. Induction of diabetes in LDL receptor (Ldlr(-/-)) knockout mice also leads to marked dyslipidemia. The reasons for this are unclear...
- Regulation of plasma fructose and mortality in mice by the aldose reductase inhibitor lidorestatHye Lim Noh
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA
J Pharmacol Exp Ther 328:496-503. 2009..If similar effects are found in humans, such treatment could improve clinical outcome in diabetic patients...