Increased oxidants are associated with insulin resistance, the metabolic syndrome, and a predisposition to atherosclerosis. This laboratory has demonstrated that the increase in oxidants causes oxidative post- translational modifications (OPTM) in key vascular cell proteins, including endothelial nitric oxide synthase (eNOS), the sarcoplasmic reticulum calcium ATPase, p21ras, and manganese superoxide dismutase. These OPTM including tyrosine nitration and cysteine sulfoxidation of specific amino acid residues have been implicated in cellular dysfunction. In an example key to endothelial function, high glucose oxidizes the redox- sensitive zinc thiolate that normally binds eNOS dimers, resulting in eNOS dysfunction. Our preliminary studies have identified another potential oxidant target, sirtuin-1 (SIRT-1), a class III histone deacetylase that is thought to be responsible for the increased life span caused by caloric restriction. Polyphenols, including the red wine component, resveratrol, directly activate SIRT-1 and mimic the effects of caloric restriction, and they have also recently been shown by others and us to reduce weight, hyperlipidemia, adhesion molecule expression, oxidants, and atherosclerosis in fat-fed mice. We discovered that polyphenols stimulate AMP- activated protein kinase (AMPK), and implicated AMPK in mediating improvements in hyperlipidemia and atherosclerosis in diabetic mice. Together with other projects within this program, we now propose that chronic oxidant stress associatedwith the metabolic syndrome can directly target and inactivate SIRT1, contributing to the down-regulation of AMPK activity and endothelial dysfunction observed in the metabolic syndrome. In addition, we propose that polyphenols stimulate SIRT1/LKB1/AMPK/ eNOS signaling to maintain endothelial function, decrease oxidants, and suppressadhesion molecule expression, apoptosis, and atherogenesis.
Our aims are to determine, 1) the role of down- and up-regulation of SIRT1/LKB1/ AMPK/eNOS signaling in mediating the effect of oxidants and the response to polyphenols, 2) what OPTM occur in SIRT-1 during exposure to oxidants, and 3) the role of SIRT1,LKB1 and eNOS in the therapeutic effect of polyphenols on inflammation, oxidants, and atherogenesis in fat-fed mice.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL068758-10
Application #
8420498
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
10
Fiscal Year
2013
Total Cost
$285,491
Indirect Cost
$86,574
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
Watanabe, Yosuke; Murdoch, Colin E; Sano, Soichi et al. (2016) Glutathione adducts induced by ischemia and deletion of glutaredoxin-1 stabilize HIF-1α and improve limb revascularization. Proc Natl Acad Sci U S A 113:6011-6
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
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
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
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
Mei, Yu; Thompson, Melissa D; Cohen, Richard A et al. (2015) Autophagy and oxidative stress in cardiovascular diseases. Biochim Biophys Acta 1852:243-51
Krasner, Nadia M; Ido, Yasuo; Ruderman, Neil B et al. (2014) Glucagon-like peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism. PLoS One 9:e97554
Shimizu, Ippei; Aprahamian, Tamar; Kikuchi, Ryosuke et al. (2014) Vascular rarefaction mediates whitening of brown fat in obesity. J Clin Invest 124:2099-112
Parker-Duffen, Jennifer L; Walsh, Kenneth (2014) Cardiometabolic effects of adiponectin. Best Pract Res Clin Endocrinol Metab 28:81-91

Showing the most recent 10 out of 98 publications