Cardiovascular Biology of Microsomal Prostaglandin E Synthase-1

Abstract

Both traditional and purpose designed nonsteroidal anti-inflammatory drugs (NSAIDs), selective for inhibition of cyclooxygenase (COX) -2 alleviate pain and inflammation but confer a cardiovascular hazard, attributable to inhibition of COX-2 derived prostacyclin (PGI2). Deletion of microsomal PGE synthase–1 (mPGES-1), the dominant enzyme that converts the COX derived intermediate product, PGH2, to form PGE2, modulates inflammatory pain in rodents. By contrast with COX-2 deletion or inhibition, PGI2 formation is augmented in mPGES-1−/− mice an effect which may confer cardiovascular benefit, yet undermine the analgesic potential of inhibitors of this enzyme. This review will consider the cardiovascular biology of mPGES1, and the complex challenge of developing inhibitors of this enzyme.

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

“…mPGES-1 is a key enzyme in inflammation, pyresis, hyperalgesia and multiple diseases with inflammatory component including rheumatoid arthritis and osteoarthritis, periodontitis, atherosclerosis, inflammatory kidney damage, stroke, multiple sclerosis and Alzheimer's disease as summarized in several excellent reviews [4,6,11,13]. Still under debate is whether mPGES-1 inhibition achieves comparable analgesic efficiency to COX inhibition since PGH 2 is redirected towards alternative pain sensitizing prostanoids, in particular PGI 2…”

“…Moreover, deletion of mPGES-1 reduced the diuretic response to acute water loading [23] and increased urine concentration after water deprivation [24] while diminishing natriuresis [25]. To which extend mPGES-1 is required to excrete an acute enteral load of sodium chloride and whether this has impact on the blood pressure is controversially discussed [13,20].…”

“…On the one hand, mPGES-1 deletion is not associated with accelerated thrombogenesis unlike Page 10 of 59 A c c e p t e d M a n u s c r i p t 10 COX-2 inhibition [26] and diminished vascular inflammation as addressed in models of atherosclerosis, abdominal aortic aneurysm and vascular injury [13,27]. The adverse role of mPGES-1 for atherosclerosis and abdominal aortic aneurysm was ascribed to mPGES-1 in myeloid cells [28,29], whereas mPGES-1 in the vasculature (smooth muscle cells and endothelial cells) did not contribute to atherogenesis and even enhanced the inflammatory response to injury [29].…”

El endotelio vascular

“…Studies which demonstrated that the enzyme converting PGH2 to PGE2, the socalled microsomal prostaglandin E synthase-1 (mPGE-1), is overexpressed in inflammation and couples with COX2 to enhance PGE2 generation. This has led more recently to the suggestion that selective inhibitors of this enzyme may be an important therapeutic target that will result in selective inhibition of the pathological PGE2, allowing PGH2 to be converted into the physiologically active prostaglandin, prostacyclin (45,46) . Overexpression of mPGE-1 has been shown in different forms of cancers and its presence is significantly correlated with a worse prognosis, at least in colorectal cancers (47,48) .…”

Amide Hydrolysis of a Novel Chemical Series of Microsomal Prostaglandin E Synthase-1 Inhibitors Induces Kidney Toxicity in the Rat

“…However, mPGES-1 inhibitors differ from COX inhibitors with respect to where in the biosynthetic cascade they inhibit PGE 2 production. It has been hypothesized that mPGES-1 inhibitors might exhibit better safety profiles due to their propensity to affect the formation of other eicosanoids than PGE 2 in a different way than conventional NSAIDs and COX-2 inhibitors (Samuelsson et al, 2007;Wang and FitzGerald 2010). However, this might also have consequences for the translational aspects of PGE 2 inhibition in pain relief (Wang and FitzGerald 2010).…”