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Hyaluronan synthase 3 promotes plaque inflammation and atheroprogression.

ABSTRACT: OBJECTIVE:Hyaluronan (HA) is a prominent component of the provisional extracellular matrix (ECM) present in the neointima of atherosclerotic plaques. Here the role of HA synthase 3 (HAS3) in atheroprogression was studied. APPROACH AND RESULTS:It is demonstrated here that HAS isoenzymes 1, -2 and -3 are expressed in human atherosclerotic plaques of the carotid artery. In Apolipoprotein E (Apoe)-deficient mice Has3 expression is increased early during lesion formation when macrophages enter atherosclerotic plaques. Importantly, HAS3 expression in vascular smooth muscle cells (VSMC) was found to be regulated by interleukin 1 ? (IL-1?) in an NFkB dependent manner and blocking antibodies to IL-1? abrogate Has3 expression in VSMC by activated macrophages. Has3/Apoe double deficient mice developed less atherosclerosis characterized by decreased Th1-cell responses, decreased IL-12 release, and decreased macrophage-driven inflammation. CONCLUSIONS:Inhibition of HAS3-dependent synthesis of HA dampens systemic Th1 cell polarization and reduces plaque inflammation. These data suggest that HAS3 might be a promising therapeutic target in atherosclerosis. Moreover, because HAS3 is regulated by IL-1?, our results suggest that therapeutic anti-IL-1? antibodies, recently tested in human clinical trials (CANTOS), may exert their beneficial effects on inflammation in post-myocardial infarction patients in part via effects on HAS3. TOC categorybasic study TOC subcategoryarteriosclerosis.

SUBMITTER: Homann S

PROVIDER: S-EPMC6023397 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Hyaluronan synthase 3 promotes plaque inflammation and atheroprogression.

Homann Susanne S Grandoch Maria M Kiene Lena S LS Podsvyadek Yanina Y Feldmann Kathrin K Rabausch Berit B Nagy Nadine N Lehr Stefan S Kretschmer Inga I Oberhuber Alexander A Bollyky Paul P Fischer Jens W JW

Matrix biology : journal of the International Society for Matrix Biology 20171005

<h4>Objective</h4>Hyaluronan (HA) is a prominent component of the provisional extracellular matrix (ECM) present in the neointima of atherosclerotic plaques. Here the role of HA synthase 3 (HAS3) in atheroprogression was studied.<h4>Approach and results</h4>It is demonstrated here that HAS isoenzymes 1, -2 and -3 are expressed in human atherosclerotic plaques of the carotid artery. In Apolipoprotein E (Apoe)-deficient mice Has3 expression is increased early during lesion formation when macrophag ...[more]

PMID: 28987865

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Project description:Acute lung injury results in early inflammation and respiratory distress, and later fibrosis. The glycosaminoglycan hyaluronan (HA) and the Receptor for Hyaluronan-Mediated Motility (RHAMM, CD168) have been implicated in the response to acute lung injury. We hypothesized that, compared to wild type (WT) mice, RHAMM knockout (KO) mice would be protected from, whereas mice with macrophage-specific transgenic overexpression of RHAMM (TG) would have worse inflammation, respiratory distress and fibrosis after intratracheal (IT) bleomycin. Compared to WT mice, 10?days after IT bleomycin, RHAMM KO mice had less weight loss, less increase in respiratory rate, and fewer CD45+ cells in the lung. At day 28, compared to injured WT animals, injured RHAMM KO mice had lower M1 macrophage content, as well as decreased fibrosis as determined by trichrome staining, Ashcroft scores and lung HPO content. Four lines of transgenic mice with selective overexpression of RHAMM in macrophages were generated using the Scavenger Receptor A promoter driving a myc-tagged full length RHAMM cDNA. Baseline expression of RHAMM and CD44 was the same in WT and TG mice. By flow cytometry, TG bone marrow-derived macrophages (BMDM) had increased cell surface RHAMM and myc, but equal CD44 expression. TG BMDM also had 2-fold increases in both chemotaxis to HA and proliferation in fetal bovine serum. In TG mice, increased inflammation after thioglycollate-induced peritonitis was restricted to macrophages and not neutrophils. For lung injury studies, non-transgenic mice given bleomycin had respiratory distress with increased respiratory rates from day 7 to 21. However, TG mice had higher respiratory rates from 4?days after bleomycin and continued to increase respiratory rates up to day 21. At 21?days after IT bleomycin, TG mice had increased lung macrophage accumulation. Lavage HA concentrations were 6-fold higher in injured WT mice, but 30-fold higher in injured TG mice. At 21?days after IT bleomycin, WT mice had developed fibrosis, but TG mice showed exaggerated fibrosis with increased Ashcroft scores and HPO content. We conclude that RHAMM is a critical component of the inflammatory response, respiratory distress and fibrosis after acute lung injury. We speculate that RHAMM is a potential therapeutic target to limit the consequences of acute lung injury.

Dataset Information

Hyaluronan synthase 3 promotes plaque inflammation and atheroprogression.

Publications

Hyaluronan synthase 3 promotes plaque inflammation and atheroprogression.

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