Plasma HDL levels have an inverse relationship with coronary heart disease, but recent failed trials of HDL raising therapies, as well as human genome wide association studies have called into the question the causal nature of this relationship. This highlights the need for a deeper mechanistic understanding of the relationship between HDL and atherosclerosis. Cholesterol efflux pathways mediated by HDL and ABC transporters act to suppress inflammation and atherosclerosis. Our recent work has defined the role of ABCA1 and ABCG1 which mediate cholesterol efflux from cells to ApoA-1 and HDL in suppressing hematopoietic stem cell proliferation, myelopoiesis, monocytosis, macrophage accumulation and inflammatory gene expression in atherosclerotic plaques. We recently discovered that ABCA1/G1 act in macrophages to suppress inflammasome activation induced by hypercholesterolemia and oxidized LDL. Moreover, macrophages deficient in ABCA1/G1 undergo pyroptotic cell death, a form of necrotic cell death that is induced by inflammasome-initiator activated caspase-1 and cytokine products of the inflammasome (IL-1).
Aim 1 will assess the effects of the inflammasome and pyroptosis on atherosclerosis in macrophages and mice with macrophage-specific knockout of ABCA1/G1, by crossing these mice with strains deficient in essential inflammasome components. Also, since we discovered elevated plasma level of inflammasome products IL-1 and IL-18 in patients with Tangier Disease, we will determine if monocytes from these subjects show evidence of inflammasome activation and pyroptosis, thus evaluating human relevance. LXR/RXR transcription factors induce ABCA1/G1 and macrophages deficient in these transporters fail to increase cholesterol efflux when treated with LXR activators. We discovered that mice with deficiency of ABCA1/G1 in macrophages nonetheless show reduced atherosclerosis when treated with LXR activators, suggesting a novel effect of LXR activators in macrophages independent of cholesterol efflux, or a vascular effect.
In Aim 2 we will seek to identify novel LXR anti-atherogenic targets in macrophages, such as genes that induce synthesis of long chain unsaturated fatty acids leading to synthesis of small proresolving lipid mediators (SPMs) that may promote resolution of atherosclerosis. An alternative explanation would be that LXRs upregulate ABCA1/G1 in endothelial cells with anti-atherogenic consequences and this will be tested in mice with endothelial-specific deficiency of these transporters. Overall, the findings are likely to contribute to the understanding of therapeutic interventions involving HDL infusions and LXR activators that are currently in human clinical trials for coronary heart disease, as well as to identify potential new therapeutic target.
HDL infusion therapies and small molecule LXR activators are in human clinical trials for coronary heart disease (CHD), but the underlying beneficial mechanisms are not well understood. The proposal will seek to investigate our novel finding that HDL and cholesterol efflux pathways suppress activation of the inflammasome in atherosclerotic plaques, using mouse models and samples from patients with Tangier Disease. In addition, we will seek to identify novel targets of LXRs in macrophages and endothelial cells that promote the resolution of inflammation and atherosclerosis and this information could help to identify new treatments for CHD.
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