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Hyaluronan synthase 3 promotes plaque inflammation and atheroprogression.

Hyaluronan synthase 3 promotes plaque inflammation and atheroprogression. Matrix biology : journal of the International Society for Matrix Biology Homann, S. n., Grandoch, M. n., Kiene, L. S., Podsvyadek, Y. n., Feldmann, K. n., Rabausch, B. n., Nagy, N. n., Lehr, S. n., Kretschmer, I. n., Oberhuber, A. n., Bollyky, P. n., Fischer, J. W. 2017

Abstract

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.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 ß (IL-1ß) in an NFkB dependent manner and blocking antibodies to IL-1ß 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.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-1ß, our results suggest that therapeutic anti-IL-1ß antibodies, currently tested in human clinical trials, may exert their beneficial effects on inflammation in post-myocardial infarction patients via effects on HAS3. in post-myocardial infarction patients who remain at high cardiovascular risk due to persistent elevated inflammatory biomarkers.

View details for DOI 10.1016/j.matbio.2017.09.005

View details for PubMedID 28987865