Dexamethasone Suppressed LPS-Induced Matrix Metalloproteinase and Its Effect on Endothelial Glycocalyx Shedding

Abstract

The aim of this study is to determine the mechanism of sepsis-induced vascular hyperpermeability and the beneficial effect of glucocorticoid in protecting vascular endothelium. Male Sprague-Dawley rats were given either a bolus intraperitoneal injection of a nonlethal dose of LPS (Escherichia coli 055:B5, 10 mg/kg, Sigma) or vehicle (pyrogen-free water). Animals of treatment groups were also given either dexamethasone (4 mg/kg, 30 min prior to LPS injection) or the matrix metalloproteinases (MMPs) inhibitor doxycycline (4 mg/kg, 30 min after LPS injection). Both activities and protein levels of MMP-2 (p < 0.001) and MMP-9 (p < 0.001) were significantly upregulated in aortic homogenates from LPS-treated rats, associated with decreased ZO-1 (p < 0.001) and syndecan-1 (p = 0.011) protein contents. Both dexamethasone and doxycycline could significantly inhibit MMPs activity and reserve the expressions of ZO-1 and syndecan-1. The inhibition of MMPs by dexamethasone was significantly lower than that by doxycycline, while the rescue of syndecan-1 expression from LPS-induced endotoxemic rat thoracic aorta was significantly higher in the dexamethasone-treated compared to the doxycycline-treated (p = 0.03). In conclusion, activation of MMPs plays important role in regulating ZO-1 and syndecan-1 protein levels in LPS mediated endothelial perturbation. Both dexamethasone and doxycycline inhibit activation of MMPs that may contribute to the rescue of ZO-1 and syndecan-1 expression.

Endothelial glycocalyx, apoptosis and inflammation in an atherosclerotic mouse model

“…Magid et al [35] showed a 3-fold increase in MMP-9 protein and mRNA expression in ECs exposed to oscillatory shear stress compared to unidirectional shear, suggesting MMP-9 expression by ECs is sensitive to flow and may contribute to the initiating events in lesion development. Cui et al [36] and Mulivor and Lipowsky [37] found that MMPs degrade glycocalyx while Lipowsky and Lescanic [38] described degradation of the glycocalyx by reactive oxygen species (ROS). Recent studies from Jo’s group [39] using an ApoE −/− mouse model with partial ligation of the left carotid artery to induce a reversing oscillatory flow field in the common carotid artery showed rapid development of atherosclerotic plaques due to a mechanism involving oscillatory shear-induced upregulation of microRNA 712 that suppresses tissue inhibitor of metalloproteinase 3, thus allowing increased MMP activity.…”

The Proteasome Inhibitor Bortezomib Inhibits Inflammatory Response of Periodontal Ligament Cells and Ameliorates Experimental Periodontitis in Rats

“…In this study, LPS was extracted by a phenol extraction method, where the endotoxin level of LPS was not <500,000 endotoxin units/mg and the protein content was <3%. The same technique has been applied previously 18 , 19 and is suitable for the current study.…”

Endothelial Response to Glucocorticoids in Inflammatory Diseases

“…GCs preserve endothelial barrier integrity through upregulation of junctional proteins such as occludin, claudin-5, and VE-cadherin (100–102) and down-regulation of MMP-9—an enzyme involved in junctional protein cleavage (103–105). GCs also induce endogenous MMP-9 inhibitors—TIMP-3 and TIMP-1 (103, 106).…”