A major feature of rupture-prone 'vulnerable' atheromata is macrophage (Mf) death, which leads to plaquenecrosis. Mf death, plaque necrosis, and coronary artery disease (CAD) are accelerated in insulin-resistantstates, including metabolic syndrome and type 2 diabetes. However,a precise understanding of how insulinresistance promotes advanced atherosclerosis at the cellular and molecular levels is lacking. The overallobjective of this proposal, within the context of the PPG, is to help shed new light in this critical area. Usingfree cholesterol (FC)-loaded Mfs as a model of advanced lesional Mf death, the Rl has elucidated a uniquemulti-hit mechanism of Mf apoptosis that involves at least 3 components: the ER stress pathway known asthe Unfolded Protein Response (UPR); the MAP kinase JNK; and a newly discovered pathway involving thefunctional interaction of the type A scavenger receptor (SRA) and toll-like receptor 4 (TLR4). Importantly, thethree Rl's'of the PPG have shown that insulin-resistant Mfs have increased SRA expression and increasedsusceptibility to SRA/ER stress-induced death both in vitro and in vivo. In another set of experiments, the Rlfound that the adipokine adiponectin, which is reduced in insulin-resistance and CAD, suppresses FC-induced UPR activation and apoptosis in Mfs.Thus, the decrease in adiponectin in insulin resistance mayrepresent another molecular-cellular link to plaque progression. With this background, Aim IA will explore thehypothesis that a unique functional interaction between SRA and TLR4 in ER-stressed Mfs triggersapoptosis. In collaboration with the other projects, we will then investigate how insulin resistance in Mfsaffects the SRA/TLR4apoptosis pathway.
In Aim I B, we will test the hypothesis that deficiency of Mf-SRAand TLR4 decreases late lesional Mf apoptosis and plaque necrosis in Ldlr-/- mice, especially in the settingof Mf insuljn resistance.
Aim HAwill elucidate the mechanisms of how adiponectin suppressesthe UPR andMf death in ER-stressedwild-type and insulin-resistant Mfs.
In Aim MB, we will test the hypotheses thatadiponectin deficiency enhances UPR activation, Mf death, and plaque necrosis in advanced lesions ofadiponectin-deficient Ldlr-/- mice and that adiponectin excess suppresses these parameters. Thus, throughextensive interactions among the 3 Rl's and the Lesion Analysis Core, this project will explore potentialmolecular-cellular links between insulin resistance and the advanced progression of atherosclerotic lesions.
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