Increasing evidence over recent years supports potential roles for subacute inflammation in the pathogenesis of cardiovascular disease as well as insulin resistance and type 2 diabetes. These diseases are themselves linked in terms of predisposition, suggesting that inflammation may form the basis of a pathogenic """"""""common soil."""""""" Our lab recently identified the inflammatory IKKbetaNF-kappaB pathway as an underlying feature of insulin resistance. We have found that (A) NF-kappaB is activated by obesity and Western diet in fat and liver, but not muscle, (B) this leads to the production of proinflammatory cytokines (e.g. IL-6, resistin, IL-1beta, TNF-alpha) and other markers and potential mediators of inflammation associated with the metabolic syndrome (e.g. CRP, PAI-1, etc.), (C) transgenic activation of NF-kappaB in fat or liver mimics these events and causes systemic insulin resistance, (D) insulin resistance is transmissible by transplanting affected fat, (E) insulin resistance is reversible by neutralizing cytokines stimulated by NF-kappaB in fat or liver, and (F), perhaps most importantly, inhibition of IKKbeta and NF-kappaB, either genetically or pharmacologically, reverses insulin resistance in animals and humans. This application proposes to test whether obesity- or Western diet-activated NF-kappaB similarly promotes vascular remodeling (i.e. whether this represents the """"""""common soil""""""""). Specifically asked questions include: (1) Does subacute """"""""inflammation"""""""" in fat or liver, at levels induced by obesity or Western diet, promote vascular remodeling? Transgenic FIKK and LIKK mice, crossed with atherosclerosis-prone Ldlr-/- and/or Apoe-/- mice, will be fed atherogenic diets and vascular lesions will be scored. (2) Does inhibition of NF-kappaB and consequent inflammation cascades in fat or liver protect mice from developing atherosclerosis? Transgenic FISR and LISR mice crossed with Ldlr-/- and/or Apoe-/- mice will test these questions. (3) A20, a target of NF-kappaB and modulator of its activity, is upregulated by Western diet and obesity. Moreover, a polymorphism in A20 confers genetic susceptibility to atherosclerosis in mice. We will determine whether altered A20 activity influences insulin resistance and vascular remodeling using knock-out and transgenic mouse technologies. (4) Does pharmacologic inhibition of NF-kappaB decrease risk for atherosclerosis? We have used salicylates extensively to inhibit NF-kappaB, reverse insulin resistance and treat diabetes in animals and humans. We now ask whether similar regimens decrease risk for the formation of vascular lesions. These studies test whether shared 'inflammatory' antecedents predispose to the development of both insulin resistance and atherosclerosis, i.e. whether obesity and dietary activation of NF-kappaB in fat and liver represent elements of the long sought """"""""common soil.""""""""

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-A)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
Ikezaki, Hiroaki; Ai, Masumi; Schaefer, Ernst J et al. (2017) Cardiovascular disease prevalence and insulin resistance in the Kyushu-Okinawa Population Study and the Framingham Offspring Study. J Clin Lipidol 11:348-356
Thongtang, Nuntakorn; Diffenderfer, Margaret R; Ooi, Esther M M et al. (2017) Metabolism and proteomics of large and small dense LDL in combined hyperlipidemia: effects of rosuvastatin. J Lipid Res 58:1315-1324
Salastekar, Ninad; Desai, Tanvi; Hauser, Thomas et al. (2017) Salsalate improves glycaemia in overweight persons with diabetes risk factors of stable statin-treated cardiovascular disease: A 30-month randomized placebo-controlled trial. Diabetes Obes Metab 19:1458-1462
Goldfine, Allison B; Shoelson, Steven E (2017) Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk. J Clin Invest 127:83-93
Elajami, Tarec K; Colas, Romain A; Dalli, Jesmond et al. (2016) Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling. FASEB J 30:2792-801
Ikezaki, Hiroaki; Ai, Masumi; Schaefer, Ernst J et al. (2016) Ethnic Differences in Glucose Homeostasis Markers between the Kyushu-Okinawa Population Study and the Framingham Offspring Study. Sci Rep 6:36725
Welty, Francine K; Alfaddagh, Abdulhamied; Elajami, Tarec K (2016) Targeting inflammation in metabolic syndrome. Transl Res 167:257-80
Asztalos, Ivor B; Gleason, Joi A; Sever, Sakine et al. (2016) Effects of eicosapentaenoic acid and docosahexaenoic acid on cardiovascular disease risk factors: a randomized clinical trial. Metabolism 65:1636-1645
Diffenderfer, Margaret R; Lamon-Fava, Stefania; Marcovina, Santica M et al. (2016) Distinct metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein(a). Metabolism 65:381-90
Hegele, Robert A; Gidding, Samuel S; Ginsberg, Henry N et al. (2015) Nonstatin Low-Density Lipoprotein-Lowering Therapy and Cardiovascular Risk Reduction-Statement From ATVB Council. Arterioscler Thromb Vasc Biol 35:2269-80

Showing the most recent 10 out of 67 publications