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Deletion of a Distal RANKL Gene Enhancer Delays Progression of Atherosclerotic Plaque Calcification in Hypercholesterolemic Mice.

ABSTRACT: Receptor activator of NF-?B ligand (RANKL) is a TNF-like cytokine which mediates diverse physiological functions including bone remodeling and immune regulation. RANKL has been identified in atherosclerotic lesions; however, its role in atherosclerotic plaque development remains elusive. An enhancer located 75?kb upstream of the murine Rankl gene's transcription start site designated D5 is important for its calciotropic hormone- and cytokine-mediated expression. Here, we determined the impact of RANKL levels in atherosclerotic plaque development in the D5 enhancer-null (D5-/- ) mice in an atherogenic Apoe-/- background fed a high-fat diet (HFD). Rankl mRNA transcripts were increased in aortic arches and thoracic aortae of Apoe-/- mice; however, this increase was blunted in Apoe-/- ;D5-/- mice. Similarly, higher Rankl transcripts were identified in splenic T lymphocytes in Apoe-/- mice, and their levels were reduced in Apoe-/- ;D5-/- mice. When analyzed by micro-computed tomography (µCT), atherosclerotic plaque calcification was identified in six out of eight Apoe-/- mice, whereas only one out of eight Apoe-/- ;D5-/- mice developed plaque calcification after 12 weeks of HFD. However, following 18 weeks of HFD challenge, all of Apoe-/- and Apoe-/- ;D5-/- animals developed atherosclerotic plaque calcification. Likewise, atherosclerotic lesion sizes were site-specifically reduced in the aortic arch of Apoe-/- ;D5-/- mice at initial stage of atherosclerosis and this effect was diminished as atherosclerosis proceeded to a more advanced stage. Our data suggest that deletion of the RANKL D5 enhancer delays the progression of atherosclerotic plaque development and plaque calcification in hypercholesterolemic mice. This work provides important insight into RANKL's regulatory role in atherosclerosis. J. Cell. Biochem. 118: 4240-4253, 2017. © 2017 Wiley Periodicals, Inc.

SUBMITTER: Shamsuzzaman S

PROVIDER: S-EPMC5645213 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Deletion of a Distal RANKL Gene Enhancer Delays Progression of Atherosclerotic Plaque Calcification in Hypercholesterolemic Mice.

Shamsuzzaman Sohel S Onal Melda M St John Hillary C HC Pike J Wesley JW

Journal of cellular biochemistry 20170530 12

Receptor activator of NF-κB ligand (RANKL) is a TNF-like cytokine which mediates diverse physiological functions including bone remodeling and immune regulation. RANKL has been identified in atherosclerotic lesions; however, its role in atherosclerotic plaque development remains elusive. An enhancer located 75 kb upstream of the murine Rankl gene's transcription start site designated D5 is important for its calciotropic hormone- and cytokine-mediated expression. Here, we determined the impact of ...[more]

PMID: 28419519

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Project description:ObjectiveCalcification of atherosclerotic plaque is traditionally associated with increased cardiovascular event risk; however, recent studies have found increased calcium density to be associated with more stable disease. 3-hydroxy-3-methylglutaryl coenzymeA reductase inhibitors or statins reduce cardiovascular events. Invasive clinical studies have found that statins alter both the lipid and calcium composition of plaque but the molecular mechanisms of statin-mediated effects on plaque calcium composition remain unclear. We recently defined a macrophage Rac (Ras-related C3 botulinum toxin substrate)-IL-1β (interleukin-1 beta) signaling axis to be a key mechanism in promoting atherosclerotic calcification and sought to define the impact of statin therapy on this pathway. Approach and Results: Here, we demonstrate that statin therapy is independently associated with elevated coronary calcification in a high-risk patient population and that statins disrupt the complex between Rac1 and its inhibitor RhoGDI (Rho GDP-dissociation inhibitor), leading to increased active (GTP bound) Rac1 in primary monocytes/macrophages. Rac1 activation is prevented by rescue with the isoprenyl precursor geranylgeranyl diphosphate. Statin-treated macrophages exhibit increased activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), increased IL-1β mRNA, and increased Rac1-dependent IL-1β protein secretion in response to inflammasome stimulation. Using an animal model of calcific atherosclerosis, inclusion of statin in the atherogenic diet led to a myeloid Rac1-dependent increase in atherosclerotic calcification, which was associated with increased serum IL-1β expression, increased plaque Rac1 activation, and increased plaque expression of the osteogenic markers, alkaline phosphatase and RUNX2 (Runt-related transcription factor 2).ConclusionsStatins are capable of increasing atherosclerotic calcification through disinhibition of a macrophage Rac1-IL-1β signaling axis.

Project description:BackgroundLipoprotein(a) [Lp(a)] is associated with increased risk of myocardial infarction, although the mechanism for this observation remains uncertain.ObjectivesThis study aims to investigate whether Lp(a) is associated with adverse plaque progression.MethodsLp(a) was measured in patients with advanced stable coronary artery disease undergoing coronary computed tomography angiography at baseline and 12 months to assess progression of total, calcific, noncalcific, and low-attenuation plaque (necrotic core) in particular. High Lp(a) was defined as Lp(a) ≥ 70 mg/dL. The relationship of Lp(a) with plaque progression was assessed using linear regression analysis, adjusting for body mass index, segment involvement score, and ASSIGN score (a Scottish cardiovascular risk score comprised of age, sex, smoking, blood pressure, total and high-density lipoprotein [HDL]-cholesterol, diabetes, rheumatoid arthritis, and deprivation index).ResultsA total of 191 patients (65.9 ± 8.3 years of age; 152 [80%] male) were included in the analysis, with median Lp(a) values of 100 (range: 82 to 115) mg/dL and 10 (range: 5 to 24) mg/dL in the high and low Lp(a) groups, respectively. At baseline, there was no difference in coronary artery disease severity or plaque burden. Patients with high Lp(a) showed accelerated progression of low-attenuation plaque compared with low Lp(a) patients (26.2 ± 88.4 mm3 vs -0.7 ± 50.1 mm3; P = 0.020). Multivariable linear regression analysis confirmed the relation between Lp(a) and low-attenuation plaque volume progression (β = 10.5% increase for each 50 mg/dL Lp(a), 95% CI: 0.7%-20.3%). There was no difference in total, calcific, and noncalcific plaque volume progression.ConclusionsAmong patients with advanced stable coronary artery disease, Lp(a) is associated with accelerated progression of coronary low-attenuation plaque (necrotic core). This may explain the association between Lp(a) and the high residual risk of myocardial infarction, providing support for Lp(a) as a treatment target in atherosclerosis.

Dataset Information

Deletion of a Distal RANKL Gene Enhancer Delays Progression of Atherosclerotic Plaque Calcification in Hypercholesterolemic Mice.

Publications

Deletion of a Distal RANKL Gene Enhancer Delays Progression of Atherosclerotic Plaque Calcification in Hypercholesterolemic Mice.

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