Ibuprofen protects human endothelial cell prostaglandin H synthase from hydrogen peroxide

Abstract

Human endothelial cells exposed to H2O2 demonstrate decreased prostacyclin (PGI2) synthesis due to decreased prostaglandin H synthase (PGH synthase) activity. We tested the hypothesis that PGH synthase activity could be protected from H2O2 by a reversible nonsteroidal anti-inflammatory drug. Experiments demonstrate that ibuprofen if present during H2O2 exposure, protects endothelial cell PGH synthase against the decrease in prostaglandin formation caused by H2O2. Additional studies demonstrated that decreasing arachidonic acid release from cell phospholipids during H2O2 exposure did not protect PGI2 synthesis following H2O2 exposure. In other experiments, ibuprofen did not chelate Fe2+ in a conformation that inhibited the reactivity of Fe2+. In addition, ibuprofen did not scavenge HO. However, we demonstrate that ibuprofen significantly protects purified PGH synthase cyclooxygenase activity from the effects of H2O2. The results confirm the hypothesis. These findings suggest that ibuprofen displaces oxidant species from the cyclooxygenase site of PGH synthase, thereby preventing oxidation of the functional groups important for PGH synthase activity.

Ibuprofen inhibits adhesiveness of monocytes to endothelium and reduces cellular oxidative stress in smokers and non‐smokers

“…Our results may be due to a modulating influence of ibuprofen on mediators linked with cigarette smoking and participating in the activation of monocytes. It has been confirmed that ibuprofen is a scavenger for the hydroxyl radical [37], protects human endothelial prostaglandin H synthase from hydrogen peroxide [38], inhibits phospholipase A2 [39] and blocks the generation of arachidonic acid metabolites by inhibiting cyclooxygenase [19]. However, one cannot exclude a direct influence of ibuprofen on the metabolism of monocytes.…”

Contractile responses elicited by hydrogen peroxide in aorta from normotensive and hypertensive rats. Endothelial modulation and mechanism involved

“…Endothelial cells can modulate the vascular responses to H 2 O 2 by generating vasoactive agents, such as nitric oxide (Monaco & Burke‐Wolin, 1995; Mohazzab‐H et al , 1996) and prostacyclin (Whorton et al , 1985; Wessels & Hempel, 1996), and by protecting smooth muscle cells from the oxidative injury mediated by H 2 O 2 (Linas & Repine, 1997). Therefore, in de‐endothelized arteries, and in hypertension, diabetes and atherosclerosis, in which endothelial cells are altered (Marín & Rodríquez‐Martínez, 1997), higher sensitivity to oxidative stress induced by H 2 O 2 could be expected.…”

Home pharmacological therapy in early COVID‐19 to prevent hospitalization and reduce mortality: Time for a suitable proposal

“…PMPs were observed also during COVID‐19; they bear a CD39 marker than can disrupt the endothelia CD39‐mediated dampening of platelet‐induced thrombosis 66 . Despite COX‐1 inhibitors may paradoxically exacerbate the production of prostacyclin from endothelia, the COX‐2 inhibitor ibuprofen resulted very efficaciously in preventing the inhibition of endothelial prostacyclin, an evidence known for many years 67–70 . In this sense, recent clinical and observational studies have highlighted how the prevalent use of COX‐2 inhibitors, in the first line of therapy in early COVID‐19, with respect to acetaminophen, reduced significantly the rate of people undergoing hospitalization 19 …”

“…66 Despite COX-1 inhibitors may paradoxically exacerbate the production of prostacyclin from endothelia, the COX-2 inhibitor ibuprofen resulted very efficaciously in preventing the inhibition of endothelial prostacyclin, an evidence known for many years. [67][68][69][70] In this sense, recent clinical and observational studies have highlighted how the prevalent use of COX-2 inhibitors, in the first line of therapy in early COVID-19, with respect to acetaminophen, reduced significantly the rate of people undergoing hospitalization. 19 From a pharmacological point of view, some authors reported recently the ability of acetaminophen to diminish the availability of reduced glutathione (GSH), a circumstance that may exacerbate the impact of the drug on platelet functions.…”