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 β (IL-1β) in an NFkB dependent manner and blocking antibodies to IL-1β 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-1β, our results suggest that therapeutic anti-IL-1β 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.

High levels of serum hyaluronan is an early predictor of dengue warning signs and perturbs vascular integrity

“…3 a). CD44 can occur as a standard form as well as several variant forms as a result of differential splicing; however, the TIME cells contain almost exclusively the standard CD44 isoform [21]. Interestingly, the transcriptional activities of HAS1 , 2 , 3 , and HYAL1 , as well as the constitutively highly expressed HYAL2 , were significantly induced after treatment of the vessel-like structures for 9 h with NS1.…”

“…In vascular tissues, hyaluronan affects smooth muscle cell proliferation [20,21], endothelial cell differentiation [[22], [23], [24]] and immune cell function [6,25,26]. Thus, hyaluronan has an important role in the regulation of vascular integrity, and its shedding from endothelial glycocalyx correlates to impaired vascular integrity during injury [27,28].…”

Deregulated expression of Elastin Microfibril Interfacer 2 (EMILIN2) in gastric cancer affects tumor growth and angiogenesis

“…More recently, much attention has been directed toward understanding the tumor microenvironment as a possible mean for the development of new therapies or predictive biomarkers [ [18] , [19] , [20] , [21] , [22] , [23] ]. One emerging promising target is the immune microenvironment, where the extracellular milieu is an important regulator [ [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] ]. The use of the immune checkpoint programmed cell death-1 (PD-1) blocking agents, the blockage of its ligands (PD-L1 or B7-H1), as well as the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), have shown remarkable therapeutic efficacy against several solid tumors [ 39 ], and may also represent a significant advance in GC treatment [ 40 ].…”

Safety of Hyaluronan 35 in Healthy Human Subjects: A Pilot Study

“…HA is synthesized by Class I HA synthetases (HAS) that are lipid-dependent membrane proteins and mammals express three HAS isozymes coded by HAS1, HAS2 and HAS3 genes [6]. Of these, HAS3 is induced by IL1β in vascular smooth muscle cells and involved in macrophage driven inflammation and atherogenic plaque progression [7] and tumor growth [8]. Degradation of large HA polymers into smaller sized fragments occurs during inflammation and processes of natural turnover [3,5].…”