Targeting Macrophage Metabolism to Treat Atherosclerosis
Researchers here propose enhancing the cellular operation of the immune cells called macrophages in order to slow the progression of atherosclerosis, a condition in which blood vessel walls become inflamed and damaged, and dangerous fatty plaques grow inside the blood vessels. A number of processes contribute to the progression of atherosclerosis once any initial damage to blood vessel walls exists, and one of the important ones is the behavior of macrophages at the site of damage. These cells are drawn by the presence of oxidatively damaged cholesterol and lipids, ingest them and break them down. Some are overwhelmed by the volume of these damaged molecules, however, becoming what are called foam cells. Many die and their debris contributes to inflammation, and the growth of plaques that narrow blood vessels. This attracts further macrophages in a vicious cycle that ends in disaster when a plaque breaks free and blocks a blood vessel to cause a stroke or heart attack. This research is focused on enhancing the ability of macrophages to deal with cholesterol:
Therapeutically targeting macrophage reverse cholesterol transport is a promising approach to treat atherosclerosis. Macrophage energy metabolism can significantly influence macrophage phenotype, but how this is controlled in foam cells is not known. Bioinformatic pathway analysis predicts that miR-33 represses a cluster of genes controlling cellular energy metabolism that may be important in macrophage cholesterol efflux. We hypothesized that cellular energy status can influence cholesterol efflux from macrophages, and that miR-33 reduces cholesterol efflux via repression of mitochondrial energy metabolism pathways.In this study, we demonstrated that macrophage cholesterol efflux is regulated by mitochondrial ATP production, and that miR-33 controls a network of genes that synchronize mitochondrial function. Inhibition of mitochondrial ATP synthase markedly reduces macrophage cholesterol efflux capacity, and anti-miR33 required fully functional mitochondria to enhance ABCA1-mediated cholesterol efflux. Specifically, anti-miR33 derepressed the novel target genes PGC-1α, PDK4, and SLC25A25 and boosted mitochondrial respiration and production of ATP. Treatment of atherosclerotic Apoe−/− mice with anti-miR33 oligonucleotides reduced aortic sinus lesion area compared with controls, despite no changes in high-density lipoprotein cholesterol or other circulating lipids. Expression of miR-33a/b was markedly increased in human carotid atherosclerotic plaques compared with normal arteries, and there was a concomitant decrease in mitochondrial regulatory genes PGC-1α, SLC25A25, NRF1, and TFAM, suggesting these genes are associated with advanced atherosclerosis in humans.
This study demonstrates that anti-miR33 therapy derepresses genes that enhance mitochondrial respiration and ATP production, which in conjunction with increased ABCA1 expression, works to promote macrophage cholesterol efflux and reduce atherosclerosis.