Hyaluronan synthase 3 promotes plaque inflammation and atheroprogression

作者：Homann Susanne; Grandoch Maria; Kiene Lena S; Podsvyadek Yanina; Feldmann Kathrin; Rabausch Berit; Nagy Nadine; Lehr Stefan; Kretschmer Inga; Oberhuber Alexander; Bollyky Paul; Fischer Jens W^*

来源：Matrix Biology, 2018, 66: 67-80.

DOI：10.1016/j.matbio.2017.09.005

• Inflammation
• Macrophage
• T-cells
• Atherosclerosis
• Hyaluronan
• Interleukin 1 beta

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

• 出版日期2018-3