ndividuals with either types I or II diabetes are 2- to 4- times more likely to develop cardiovascular disease (CVD) than 1on-diabetics. This risk is particularly high among those with hyperglycemia, and probably insulin resistance, and it ,_scapes quantification based upon traditional CVD risk factors alone. One emerging feature of diabetes is an excess of oxidative stress that, in the vasculature, has a number of important sequelae including altered NO bioactivity, increase( adhesion molecule expression, and the promotion of atherosclerotic lesion formation. The precise mechanism(s) whereby oxidative stress promotes these phenotypic characteristics of vascular disease are not known. In preliminary data presented here, we have found that two hallmarks of types I and II diabetes, hyperglycemia and elevated free fatt3 acids (FFAs), impart an oxidative stress in cultured endothelial cells that mediates several maladaptive responses including insulin resistance, eNOS-mediated oxidant production, and reduced NO bioactivity. We have also demonstrated AMP kinase activation in response to oxidative stress that we view as a central for the cellular adaptatiol to oxidative stress The goal of this proposal is to determine the role of AMP kinase activation in the phenotypic _bnormalities of the endothelium promoted by oxidative stress due to excess glucose and FFAs. To accomplish this oal, we will first characterize the nature of the oxidative stress due to hyperglycemia/FFAs with particular attention tt the mitochondrion, NADPH oxidase, and eNOS as sources of this oxidative stress. We will then work in close collaboration with Project 1 to determine if oxidative stress is a cause or consequence of changes in cellular metabolism due to hyperglycemia/FFAs. We will then be in a position to determine how cellular metabolism and oxidative stress from hyperglycemia/FFAs relate to endothelial cell insulin resistance and Akt signaling. Since AMP kinase is a key factor in cellular adaptation to stress, we will then characterize the activation of AMP kinase by hyperglycemia/FFAs and the role of oxidative stress in this process. The molecular consequences of AMP kinase activation will also be determined in order to gain insight into the mechanisms of reduced oxidative stress by AMP kinase activation. Finalb we will determine the consequences of hyperglycemia/FFAs for endothelial cell NO bioactivity with particular attention to eNOS phosphorylation status and the resultant consequences for catalytic activity and eNOS-mediated oxidant production. Using this approach, we should be able to define the pathologic events associated with hyperglycemia an, FFAs that contribute to diabetic CVD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL068758-05
Application #
7441024
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
5
Fiscal Year
2007
Total Cost
$290,383
Indirect Cost
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
Vikram, Ajit; Lewarchik, Christopher M; Yoon, Jin-Young et al. (2017) Sirtuin 1 regulates cardiac electrical activity by deacetylating the cardiac sodium channel. Nat Med 23:361-367
Shao, Di; Han, Jingyan; Hou, Xiuyun et al. (2017) Glutaredoxin-1 Deficiency Causes Fatty Liver and Dyslipidemia by Inhibiting Sirtuin-1. Antioxid Redox Signal 27:313-327
Watanabe, Yosuke; Murdoch, Colin E; Sano, Soichi et al. (2016) Glutathione adducts induced by ischemia and deletion of glutaredoxin-1 stabilize HIF-1? and improve limb revascularization. Proc Natl Acad Sci U S A 113:6011-6
Ji, Yuhuan; Bachschmid, Markus M; Costello, Catherine E et al. (2016) S- to N-Palmitoyl Transfer During Proteomic Sample Preparation. J Am Soc Mass Spectrom 27:677-85
Peskin, Alexander V; Pace, Paul E; Behring, Jessica B et al. (2016) Glutathionylation of the Active Site Cysteines of Peroxiredoxin 2 and Recycling by Glutaredoxin. J Biol Chem 291:3053-62
Yao, Chunxiang; Behring, Jessica B; Shao, Di et al. (2015) Overexpression of Catalase Diminishes Oxidative Cysteine Modifications of Cardiac Proteins. PLoS One 10:e0144025
Weikel, Karen A; Cacicedo, José M; Ruderman, Neil B et al. (2015) Glucose and palmitate uncouple AMPK from autophagy in human aortic endothelial cells. Am J Physiol Cell Physiol 308:C249-63
Nolan, Christopher J; Ruderman, Neil B; Kahn, Steven E et al. (2015) Insulin resistance as a physiological defense against metabolic stress: implications for the management of subsets of type 2 diabetes. Diabetes 64:673-86
Mei, Yu; Thompson, Melissa D; Cohen, Richard A et al. (2015) Autophagy and oxidative stress in cardiovascular diseases. Biochim Biophys Acta 1852:243-51
Akasaki, Yuichi; Ouchi, Noriyuki; Izumiya, Yasuhiro et al. (2014) Glycolytic fast-twitch muscle fiber restoration counters adverse age-related changes in body composition and metabolism. Aging Cell 13:80-91

Showing the most recent 10 out of 101 publications