High Glucose Causes Upregulation of Cyclooxygenase-2 and Alters Prostanoid Profile in Human Endothelial Cells

Abstract

Background-Prostaglandins generated by cyclooxygenase (COX) have been implicated in hyperglycemia-induced endothelial dysfunction. However, the role of individual COX isoenzymes as well as the molecular mechanisms linking oxidative stress and endothelial dysfunction in diabetes remains to be clarified. Methods and Results-Human aortic endothelial cells were exposed to normal (5.5 mmol/L) and high (22.2 mmol/L) glucose. Glucose selectively increased mRNA and protein expression of COX-2. Its upregulation was associated with an increase of thromboxane A 2 and a reduction of prostacyclin (PGI 2 ) release. Glucose-induced activation of PKC resulted in the formation of peroxynitrite and tyrosine nitration of PGI 2 synthase. NO release was reduced despite 2-fold increase of endothelial NO synthase expression. Phorbol ester caused an increase of COX-2 and endothelial NO synthase expression similar to that elicited by glucose. These effects were prevented by the PKC inhibitor calphostin C. N-acetylcysteine, vitamin C, and calphostin C prevented ROS formation, restored NO release, and reduced colocalization of nitrotyrosine and PGI 2 synthase. Expression of p22 phox , a subunit of NAD(P)H oxidase, was increased, and diphenyleneiodonium inhibited ROS formation. By contrast, indomethacin did not affect glucose-induced ROS generation. Conclusions-Thus, high glucose, via PKC signaling, induces oxidative stress and upregulation of COX-2, resulting in reduced NO availability and altered prostanoid profile.

Nitric oxide, oxidants, and protein tyrosine nitration

“…Formation of peroxynitrite might also play subtle roles in signal transduction processes (36)(37)(38)(39). However, identification of oxidation and nitration products in conjunction with pharmacological and͞or genetic approaches has substantiated direct toxicity of peroxynitrite in pathophysiologically relevant conditions (see ref.…”

Oxygen‐derived free radicals mediate endothelium‐dependent contractions in femoral arteries of rats with streptozotocin‐induced diabetes

“…This is due to the increased production of free radicals and/or impaired antioxidant defences. Mechanisms underlying the increased oxidative stress in diabetes include activation of transcription factors, protein kinase C, glucose oxidation and augmented production of advanced glycated end products (Bucala et al, 1991;Alp et al, 2003;Cosentino et al, 2003;Wong et al, 2003;Sheu et al, 2005;Ho et al, 2006). The evidence suggesting a reduced antioxidant defence in arteries from animals with streptozotocin (STZ)-induced diabetes includes the reduced activity of superoxide dismutase (SOD) and catalase, and a decreased presence or bioavailability of glutathione and nitric oxide (Mekinova et al, 1995;Aragno et al, 1999;Kedziora-Kornatowska et al, 2000;Rauscher et al, 2001;Maritim et al, 2003).…”

Insulin-like growth factor-I induces cyclooxygenase-2 expression via PI3K, MAPK and PKC signaling pathways in human ovarian cancer cells☆

“…PKC activity regulated COX-2 expression induced by inflammatory stimuli and stress signals (16,19,47,49,50). Activation of PKC promotes COX-2 gene transcription through the transcription factors NF-κB and C/EBP (16,50).…”