Macrophage mitochondrial energy status regulates cholesterol efflux and is enhanced by anti-miR33 in atherosclerosis

D Karunakaran, AB Thrush, MA Nguyen… - Circulation …, 2015 - Am Heart Assoc
D Karunakaran, AB Thrush, MA Nguyen, L Richards, M Geoffrion, R Singaravelu
Circulation research, 2015Am Heart Assoc
Rationale: 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. Objective: We hypothesized that cellular energy status can influence cholesterol efflux …
Rationale:
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.
Objective:
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.
Methods and Results:
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.
Conclusions:
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.
Am Heart Assoc