Although a wealth of epidemiological studies indicate that high levels of HDL-C are associated with protection from cardiovascular disease, the recent failure of HDL-raising therapies at reducing clinical events has called the entire HDL paradigm into question. These studies underscore the critical need to better understand the mechanisms by which HDL exerts its atheroprotective effects, so that we can design therapeutics that harness these properties and provide maximum clinical benefit. Experimental studies in animals and humans indicate that therapies that increase the number of HDL particles or promote reverse cholesterol transport (RCT) confer atheroprotection. A major advance in our understanding of the regulation of HDL biogenesis and cholesterol efflux came from the identification by our lab and others those microRNA-33a/b (miR-33) represses key genes in these pathways, including ABCA1, ABCG1, NPC1. In preclinical studies in mice and non-human primates we showed that inhibition of miR-33 increases HDL-C, promotes RCT and regresses atherosclerotic plaques. These translational studies identify miR-33 pathway inhibition as a novel therapeutic strategy for targeting the HDL pathway, that is particularly promising as it increases both HDL biogenesis and reverse cholesterol transport, however the complete mechanisms by which anti-miR33 exerts its beneficial effects on HDL levels and functionality are not yet understood. There is thus a strong rationale to undertake a comprehensive analysis of miR-33 targeted pathways that generate an increased functional HDL particle to promote RCT and induce atherosclerosis regression.
The aims proposed herein will identify new players in the miR-33 pathway that regulate HDL biogenesis/RCT and determine the target tissues responsible for the atheroprotective effects of anti-miR33. Together, these studies will enhance our understanding of the mechanisms of action of anti- miR-33 pathway inhibition, and provide important insight into the potential of this novel therapy for improving HDL functionality in treatment of cardiometabolic diseases.
While epidemiological studies indicate that high levels of high density lipoprotein cholesterol (HDL-C) are associated with protection from cardiovascular disease, there is a need to better understand the mechanisms by which HDL exerts its protective effects, so that we can design therapeutics that harness these properties. Recent studies identify miR-33 pathway inhibition as a novel therapeutic strategy for targeting the HDL pathway, yet the complete mechanisms by which anti-miR33 exerts its beneficial effects are not yet understood. We will undertake a comprehensive analysis of miR-33 targeted pathways to identify novel pathways that increase HDL levels and reverse cholesterol transport.
| van Solingen, Coen; Scacalossi, Kaitlyn R; Moore, Kathryn J (2018) Long noncoding RNAs in lipid metabolism. Curr Opin Lipidol 29:224-232 |
| Nguyen, My-Anh; Karunakaran, Denuja; Geoffrion, Michèle et al. (2018) Extracellular Vesicles Secreted by Atherogenic Macrophages Transfer MicroRNA to Inhibit Cell Migration. Arterioscler Thromb Vasc Biol 38:49-63 |
| Scacalossi, Kaitlyn R; van Solingen, Coen; Moore, Kathryn J (2018) Long non-coding RNAs regulating macrophage functions in homeostasis and disease. Vascul Pharmacol : |
| Laffont, Benoit; Rayner, Katey J (2017) MicroRNAs in the Pathobiology and Therapy of Atherosclerosis. Can J Cardiol 33:313-324 |
| Kavurma, Mary M; Rayner, Katey J; Karunakaran, Denuja (2017) The walking dead: macrophage inflammation and death in atherosclerosis. Curr Opin Lipidol 28:91-98 |
| Maus, Mate; Cuk, Mario; Patel, Bindi et al. (2017) Store-Operated Ca2+ Entry Controls Induction of Lipolysis and the Transcriptional Reprogramming to Lipid Metabolism. Cell Metab 25:698-712 |
| Rayner, Katey J (2017) Cell Death in the Vessel Wall: The Good, the Bad, the Ugly. Arterioscler Thromb Vasc Biol 37:e75-e81 |
| Ouimet, Mireille; Ediriweera, Hasini; Afonso, Milessa Silva et al. (2017) microRNA-33 Regulates Macrophage Autophagy in Atherosclerosis. Arterioscler Thromb Vasc Biol 37:1058-1067 |
| Feinberg, Mark W; Moore, Kathryn J (2016) MicroRNA Regulation of Atherosclerosis. Circ Res 118:703-20 |
| Ouimet, Mireille; Hennessy, Elizabeth J; van Solingen, Coen et al. (2016) miRNA Targeting of Oxysterol-Binding Protein-Like 6 Regulates Cholesterol Trafficking and Efflux. Arterioscler Thromb Vasc Biol 36:942-951 |
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