NF-KB, Inflammation and Vascular Remodeling

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Linked publications & trials

Abstract

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