Cyclooxygenase inhibitors repress vascular hyaluronan‐synthesis in murine atherosclerosis and neointimal thickening

Abstract

Hyaluronan (HA) is a key molecule of the extracellular matrix that is thought to be critically involved in both atherosclerosis and restenosis. Recently, it has been demonstrated that the cyclooxygenase (COX) products, prostacyclin and prostaglandin E2, induce HA synthesis in vitro by transcriptional up-regulation of HA-synthase 2 (HAS2) and HAS1. The relative roles in atherosclerotic and restenotic artery disease of tissue specifically expressed COX-1 and COX-2 are still under debate. Thus, the present study aimed to investigate the effect of COX isoform inhibition on HA-accumulation and regulation of HAS isoform expression in two models of pathologic artery remodelling in vivo. Firstly, ApoE-deficient mice were treated with a prototypic isoform non-selective inhibitor, indomethacin or with a prototypic COX-2 selective inhibitor, rofecoxib, for 8 weeks. Aortic HAS mRNA expression and HA-accumulation in atherosclerotic aortic root lesions were analyzed. Secondly, neointimal hyperplasia was induced by carotid artery ligation in ApoE-deficient mice on a high fat diet and the effects of the COX inhibitors were determined after 4 weeks of treatment. Intimal HA-accumulation was markedly reduced in both models by indomethacin and rofecoxib. This coincided with a strong inhibition of HAS1 mRNA expression in both models and with decreased HAS2 mRNA in the aorta of ApoE-deficient mice. HAS3 was not affected. The repression of HA-accumulation by both COX-2 selective and non-selective COX inhibition implicates COX-2 in the regulation of HA synthesis via stimulation of HAS1 and HAS2 expression in vivo. Modulation of vascular HA-accumulation might play a role in chronic effects of COX inhibitors on the progression of atherosclerosis.

Hyaluronan turnover and hypoxic brown adipocytic differentiation are co-localized with ossification in calcified human aortic valves

“…HA itself appears to have a complicated relationship with calcification, with some reports suggesting that HA promotes the late osteogenic differentiation of cells [38] while others have integrated HA into biomaterial scaffolds and found either enhancement [15] or prevention [22, 25] of mineralization. Although there are no published investigations of the HA synthases in adult valves, the signaling pathways regulating the activity of HAS-1, HAS-2, and HAS-3 represent therapeutic targets for atherosclerosis [17] and potentially for CAVD as well. Further study of the dynamic synthesis and degradation of HA in heart valves, and how these mechanisms contribute to valve calcification in vitro and in vivo, will be necessary.…”

MyD88 signaling promotes both mucosal homeostatic and fibrotic responses during Salmonella-induced colitis

“…To investigate whether Cox-2 contributed to the pathologies seen in this model, we inhibited Cox-2 by treating WT mice daily with an oral dose of 20 mg/kg rofecoxib, a Cox-2-specific inhibitor (25), during a 7-day infection, while a control group only received the carrier. As assessed at postinfection day 7, rofecoxib treatment was unable to significantly reduce epithelial cell proliferation (not shown).…”

Mast Cell-derived Prostaglandin D2 Controls Hyaluronan Synthesis in Human Orbital Fibroblasts via DP1 Activation

“…Increased HA synthesis closely correlates with the expression levels of HAS (7), which are themselves induced by growth factors, cytokines (7)(8)(9), and prostaglandins (PGs) (10,11). One PG that may have an important implication in TED is PGD 2 .…”