The risk of coronary heart disease (CHD), the largest major killer of Americans, is inversely associated with high-density lipoprotein cholesterol (HDL-C). The protective effects of HDL-C are believed to be due to the role of HDL in reverse cholesterol transport (RCT), a process whereby cholesterol from macrophage foam cells in atherosclerotic plaques is effluxed to HDL, transported to the liver, and excreted in the feces. Despite intense efforts to identify new therapeutic strategies to raise HDL, this has proven to be a challenging endeavor. A new and promising target for increasing HDL-C and RCT is microRNA-33 (miR-33). In humans, two isoforms of this microRNA, miR-33a and miR-33b, are encoded in introns of the sterol response element binding factor (SREBF) 2 and SREBF1 genes, and co-regulate cellular lipid homeostasis with their host genes. Notably, miR-33a/b induce mRNA degradation and/or translational repression of genes involved in cholesterol efflux and fatty acid oxidation. A major target of miR-33a/b is the ATP binding cassette transporter A1 (ABCA1), a protein essential for cholesterol efflux from foam cells and the formation of HDL. In mice, which encode only miR-33a, an antisense oligonucleotide targeting miR-33 (anti-miR-33) increased hepatic and macrophage ABCA1, HDL-C, RCT, and atherosclerosis regression. However the translational value of the studies in mice was limited by the lack of miR-33b, which is expressed in humans and non-humans primates. To test the effects of inhibiting both miR-33a and b, we recently treated African green monkeys with anti-miR- 33 and found that hepatic ABCA1 and HDL-C was elevated and very low-density lipoprotein (VLDL) triglyceride was decreased. While the preclinical findings to date highlight the cardioprotective potential of anti-miR-33, the ability of anti-miR-33 to induce the regression of atherosclerosis in a """"""""human-like"""""""" species expressing both miR-33a and miR-33b is still unknown. In this application, we propose to determine the effects of anti-miR-33 on atherosclerosis regression and RCT in non-human primates. These studies will greatly aid in assessing anti-miR-33 as a potential clinical treatment for CHD.
High density lipoprotein (HDL) cholesterol concentration is a strong, inversely related risk factor for coronary heart disease (CHD), the largest major killer of Americans. Therapies that raise HDL cholesterol have the potential to reduce the risk of CHD. We propose to determine how treatment of non-human primates with anti- miR-33 affects not only HDL function and composition but also the regression of atherosclerosis.
|Temel, Ryan E; Brown, J Mark (2015) A new model of reverse cholesterol transport: enTICEing strategies to stimulate intestinal cholesterol excretion. Trends Pharmacol Sci 36:440-51|
|Zhang, Hanrui; Temel, Ryan E; Martel, Catherine (2014) Cholesterol and lipoprotein metabolism: Early Career Committee contribution. Arterioscler Thromb Vasc Biol 34:1791-4|
|Hong, Cynthia; Marshall, Stephanie M; McDaniel, Allison L et al. (2014) The LXR-Idol axis differentially regulates plasma LDL levels in primates and mice. Cell Metab 20:910-8|