Hyaluronan synthase 3 promotes plaque inflammation and atheroprogression.
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. TOC categorybasic study TOC subcategoryarteriosclerosis.
['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|']
D000818:Animals D001057:Apolipoproteins E D016764:Cell Polarity D002478:Cells, Cultured D004195:Disease Models, Animal D018450:Disease Progression D006801:Humans D000076002:Hyaluronan Synthases D006820:Hyaluronic Acid D053583:Interleukin-1beta D008264:Macrophages D051379:Mice D009131:Muscle, Smooth, Vascular D032389:Myocytes, Smooth Muscle D016328:NF-kappa B D058226:Plaque, Atherosclerotic D018417:Th1 Cells
Hyaluronan Inflammation Macrophage Atherosclerosis Interleukin 1 beta T-cells Vascular Biology