Reactive oxygen species mediate high glucose-induced heparanase-1 production and heparan sulphate proteoglycan degradation in human and rat endothelial cells: a potential role in the pathogenesis of atherosclerosis

Abstract

Aims/hypothesis The content of heparan sulphate is reduced in the endothelium under hyperglycaemic conditions and may contribute to the pathogenesis of atherosclerosis. Heparanase-1 (HPR1) specifically degrades heparan sulphate proteoglycans. We therefore sought to determine whether: (1) heparan sulphate reduction in endothelial cells is due to increased HPR1 production through increased reactive oxygen species (ROS) production; and (2) HPR1 production is increased in vivo in endothelial cells under hyperglycaemic and/or atherosclerotic conditions. Methods HPR1 mRNA and protein levels in endothelial cells were analysed by RT-PCR and Western blot or HPR1 enzymatic activity assay, respectively. Cell surface heparan sulphate levels were analysed by FACS. HPR1 in the artery from control rats and a rat model of diabetes, and from patients under hyperglycaemic and/or atherosclerotic conditions was immunohistochemically examined. Results High-glucose-induced HPR1 production and heparan sulphate degradation in three human endothelial cell lines, both of which were blocked by ROS scavengers, glutathione and N-acetylcysteine. Exogenous H 2 O 2 induced HPR1 production, subsequently leading to decreased cell surface heparan sulphate levels. HPR1 content was significantly increased in endothelial cells in the arterial walls of a rat model of diabetes. Clinical studies revealed that HPR1 production was increased in endothelial cells under hyperglycaemic conditions, and in endothelial cells and macrophages in atherosclerotic lesions.

Heparanase Expression in Renal Interstitial May Contribute to Epithelial and Endothelial Cells Injuries After Kidney Ischemic/ Reperfusion Episode in Mice

“…Previously, we reported that kidney I/R induced ROS production that is inhibited by ET-1 deletion from endothelial cells (Arfian et al, 2012). Our results are consistent with several studies that reported about the role of ROS in mediating heparanase production, particularly in high glucose condition (Rao et al, 2011), as well as aldosteron and angiotensin II treatment in glomerulus (van den Hoven et al, 2009). Because of ROS has different role in the epithelial and interstitial cells after kidney I/R injury (Kim et al, 2010), it seem that heparanase also regulate those cells differently.…”

“…Loss of glomerular endothelial glycocalyx in adriamycin nephropathy model associated with down regulation of HS and enzymes that play role in synthesis and elongation of proteoglycan GAG chains (Jeansson et al, 2009). HS loss is also induced by heparanase production, an endoglycosidase that degrades HS (Rao et al, 2011). In this study, we observed an increase of heparanase expression in extension phase of kidney I/R injury (Fig.3).…”

“…An increase of heparanase also occurs after focal cerebral ischemic in the mouse brain and correlates with proliferating endothelial cells undergoing angiogenesis (Li et al, 2012). Heparanase up-regulation in endothelial cells and macrophages is suggested to play role in reduction of HS amount in arterial wall and contributes to atherosclerosis (Rao et al, 2011). It seem that high expression of heparanase after kidney I/R injury leads to endothelial dysfunction with eNOS reduction and glycocalyx disruption.…”

LDL as a Cause of Atherosclerosis

“…They suggest that these changes may be associated with higher membrane fluidity and higher freedom in lateral movement thus allowing Apo B to acquire a conformation which is more favorable for proteoglycan binding. The heparin sulphate proteoglycans (HSPG) play an important role in the assembly and structure of the basement membrane [79]. There is evidence that HSPG is reduced under hyperglycaemic conditions [80].…”

“…Loss of arterial heparin sulphate correlates with the onset of atherosclerosis in a monkey model of diabetes [81]. Recently, Rao et al, [79] have shown that hyperglycaemia induces heparin sulphate degradation through increase reactive oxygen production via increase in heparanase 1 which specifically degrades heparin sulphate proteoglycans thus a vicious circle is set up in which an increase in free radical production increases oxidation and Lp (a) aggregation and in turn stimulates inflammatory molecules such as tumor necrosis factor-(TNF ) and interleukan6 (IL-6) and increase free radical production. Heparanase-1 is produced locally by the endothelium.…”