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HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells.

ABSTRACT: HDL cholesterol (HDL-C) plasma levels are inversely related to cardiovascular disease risk. Previous studies have shown in animals and humans that HDL promotes regression of atherosclerosis. We hypothesized that this was related to an ability to promote the loss of monocyte-derived cells (CD68(+), primarily macrophages and macrophage foam cells) from plaques. To test this hypothesis, we used an established model of atherosclerosis regression in which plaque-bearing aortic arches from apolipoprotein E-deficient (apoE(-/-)) mice (low HDL-C, high non-HDL-C) were transplanted into recipient mice with differing levels of HDL-C and non-HDL-C: C57BL6 mice (normal HDL-C, low non-HDL-C), apoAI(-/-) mice (low HDL-C, low non-HDL-C), or apoE(-/-) mice transgenic for human apoAI (hAI/apoE(-/-); normal HDL-C, high non-HDL-C). Remarkably, despite persistent elevated non-HDL-C in hAI/apoE(-/-) recipients, plaque CD68(+) cell content decreased by >50% by 1 wk after transplantation, whereas there was little change in apoAI(-/-) recipient mice despite hypolipidemia. The decreased content of plaque CD68(+) cells after HDL-C normalization was associated with their emigration and induction of their chemokine receptor CCR7. Furthermore, in CD68(+) cells laser-captured from the plaques, normalization of HDL-C led to decreased expression of inflammatory factors and enrichment of markers of the M2 (tissue repair) macrophage state. Again, none of these beneficial changes were observed in the apoAI(-/-) recipients, suggesting a major requirement for reverse cholesterol transport for the beneficial effects of HDL. Overall, these results establish HDL as a regulator in vivo of the migratory and inflammatory properties of monocyte-derived cells in mouse atherosclerotic plaques, and highlight the phenotypic plasticity of these cells.

SUBMITTER: Feig JE

PROVIDER: S-EPMC3084076 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells.

Feig Jonathan E JE Rong James X JX Shamir Raanan R Sanson Marie M Vengrenyuk Yuliya Y Liu Jianhua J Rayner Katey K Moore Kathryn K Garabedian Michael M Fisher Edward A EA

Proceedings of the National Academy of Sciences of the United States of America 20110411 17

HDL cholesterol (HDL-C) plasma levels are inversely related to cardiovascular disease risk. Previous studies have shown in animals and humans that HDL promotes regression of atherosclerosis. We hypothesized that this was related to an ability to promote the loss of monocyte-derived cells (CD68(+), primarily macrophages and macrophage foam cells) from plaques. To test this hypothesis, we used an established model of atherosclerosis regression in which plaque-bearing aortic arches from apolipoprot ...[more]

PMID: 21482781

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Project description:BACKGROUND:Despite robust cholesterol lowering, cardiovascular disease risk remains increased in patients with diabetes mellitus. Consistent with this, diabetes mellitus impairs atherosclerosis regression after cholesterol lowering in humans and mice. In mice, this is attributed in part to hyperglycemia-induced monocytosis, which increases monocyte entry into plaques despite cholesterol lowering. In addition, diabetes mellitus skews plaque macrophages toward an atherogenic inflammatory M1 phenotype instead of toward the atherosclerosis-resolving M2 state typical with cholesterol lowering. Functional high-density lipoprotein (HDL), typically low in patients with diabetes mellitus, reduces monocyte precursor proliferation in murine bone marrow and has anti-inflammatory effects on human and murine macrophages. Our study aimed to test whether raising functional HDL levels in diabetic mice prevents monocytosis, reduces the quantity and inflammation of plaque macrophages, and enhances atherosclerosis regression after cholesterol lowering. METHODS:Aortic arches containing plaques developed in Ldlr-/- mice were transplanted into either wild-type, diabetic wild-type, or diabetic mice transgenic for human apolipoprotein AI, which have elevated functional HDL. Recipient mice all had low levels of low-density lipoprotein cholesterol to promote plaque regression. After 2 weeks, plaques in recipient mouse aortic grafts were examined. RESULTS:Diabetic wild-type mice had impaired atherosclerosis regression, which was normalized by raising HDL levels. This benefit was linked to suppressed hyperglycemia-driven myelopoiesis, monocytosis, and neutrophilia. Increased HDL improved cholesterol efflux from bone marrow progenitors, suppressing their proliferation and monocyte and neutrophil production capacity. In addition to reducing circulating monocytes available for recruitment into plaques, in the diabetic milieu, HDL suppressed the general recruitability of monocytes to inflammatory sites and promoted plaque macrophage polarization to the M2, atherosclerosis-resolving state. There was also a decrease in plaque neutrophil extracellular traps, which are atherogenic and increased by diabetes mellitus. CONCLUSIONS:Raising apolipoprotein AI and functional levels of HDL promotes multiple favorable changes in the production of monocytes and neutrophils and in the inflammatory environment of atherosclerotic plaques of diabetic mice after cholesterol lowering and may represent a novel approach to reduce cardiovascular disease risk in people with diabetes mellitus.

Project description:BackgroundAtherosclerotic plaque instability is a common cause of stroke and ischemic infarction, and identification of monocyte-associated genes has become a prominent feature in cardiovascular research as a contributing/predictive marker.MethodsWhole genome sequencing data were downloaded from GSE159677, GSE41571, GSE120521, and GSE118481. Single-cell sequencing data analysis was conducted to cluster molecular subtypes of atherosclerotic plaques and identify specific genes. Differentially expressed genes (DEGs) between normal subjects and patients with unstable atheromatous plaques were screened. Weighted gene coexpression network analysis (WGCNA) was performed to find key module genes. In addition, GO and KEGG enrichment analyses explored potential biological signaling pathways to generate protein interaction (PPI) networks. GSEA and GSVA demonstrated activations in plaque instability subtypes.Results239 monocyte-associated genes were identified based on bulk and single-cell RNA-sequencing, followed by the recognition of 1221 atherosclerotic plaque-associated DEGs from the pooled matrix. GO and KEGG analyses suggested that DEGs might be related to inflammation response and the PI3K-Akt signaling pathway. Eight no-grey modules were obtained through WGCNA analysis, and the turquoise module has the highest correlation with unstable plaque (R 2 = 0.40), which contained 1323 module genes. After fetching the intersecting genes, CXCL3, FPR1, GK, and LST1 were obtained that were significantly associated with plaque instability, which had an intense specific interaction. Monocyte-associated genes associated with atherosclerotic plaque instability have certain diagnostic significance and are generally overexpressed in this patient population. In addition, 11 overlapping coexpressed genes (CEG) might also activated multiple pathways regulating inflammatory responses, platelet activation, and hypoxia-inducible factors. GSVA showed that the corresponding pathways were significantly activated in high expression samples.ConclusionsOverexpression of CXCL3, GK, FPR1, and LST1 was advanced recognition and intervention factors for unstable plaques, which might become targets for atherosclerosis rupture prevention. We also analyzed the potential mechanisms of CEG from inflammatory and oxidative stress pathways.

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HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells.

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HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells.

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