An Update of Microsomal Prostaglandin E Synthase‐1 and PGE₂ Receptors in Cardiovascular Health and Diseases

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs), especially cyclooxygenase-2 (COX-2) selective inhibitors, are among the most widely used drugs to treat pain and inflammation. However, clinical trials have revealed that these inhibitors predisposed patients to a significantly increased cardiovascular risk, consisting of thrombosis, hypertension, myocardial infarction, heart failure, and sudden cardiac death. Thus, microsomal prostaglandin E (PGE) synthase-1 (mPGES-1), the key terminal enzyme involved in the synthesis of inflammatory prostaglandin E2 (PGE2), and the four PGE2 receptors (EP1–4) have gained much attention as alternative targets for the development of novel analgesics. The cardiovascular consequences of targeting mPGES-1 and the PGE2 receptors are substantially studied. Inhibition of mPGES-1 has displayed a relatively innocuous or preferable cardiovascular profile. The modulation of the four EP receptors in cardiovascular system is diversely reported as well. In this review, we highlight the most recent advances from our and other studies on the regulation of PGE2, particularly mPGES-1 and the four PGE2 receptors, in cardiovascular function, with a particular emphasis on blood pressure regulation, atherosclerosis, thrombosis, and myocardial infarction. This might lead to new avenues to improve cardiovascular disease management strategies and to seek optimized anti-inflammatory therapeutic options.

Epigenetic control of microsomal prostaglandin E synthase-1 by HDAC-mediated recruitment of p300

“…The lipid mediator has diverse functions, including cytoprotection in the gastrointestinal tract, modulation of the immune system, and induction of the febrile responses. Furthermore, in the vascular system, PGE 2 reduced smooth muscle tone and changed proliferation and inflammatory activity (20)(21)(22)(23). Here, we observed that HDACi reduced the vascular PGE 2 level in the carotid, which resulted in attenuated arachidonic acid-induced relaxation suggesting an attenuated conversion of arachidonic acid to the vasodilator, PGE 2 (12,14,15).…”

Prostaglandin E2 Activates NLRP3 Inflammasome in Endothelial Cells to Promote Diabetic Retinopathy

“…In our study, various pro-inflammatory cytokines are highly expressed in the vitreous of PDR patients, indicating that inflammation may play an essential role in PDR progression. PGE 2 , a naturally occurring prostaglandin, serves as a key regulator involved in the inflammatory process in the cardiovascular system [31]. Inflammation in vascular diseases involves infiltrating inflammatory cells, circulating cells, immune cells and constitutive cells of vascular tissues.…”

Prostaglandin E2 increases migration and proliferation of human glioblastoma cells by activating transient receptor potential melastatin 7 channels

“…17‐pt‐PGE2 was purchased from Cayman chemical. PGE2, 2‐Acetylhydrazide‐10(11H)‐carboxylic acid, 8‐Chloro‐dibenz [b, f] oxazepine‐10(11H)‐carboxylic acid (SC19220), (4Z)‐7‐[(rel‐1S,2S,5R)‐5‐((1,1′‐Biphenyl‐4‐yl)methoxy)‐ ‐2‐(4‐morpholinyl)‐3‐oxocyclopentyl]‐4‐heptenoic acid hemicalcium salt (AH23848), (2E)‐N‐[(5‐bromo‐2‐methoxyphenyl)sulfonyl]‐3‐[2‐(2‐naphthalenylmethyl)phenyl]‐2‐propenamide (L‐798106), 6‐isopropoxy‐9‐xanthone‐2‐carboxylic acid (AH6809), Dibutyryl‐cAMP (Db‐cAMP), Rp‐cAMP (Rp‐Adenosine 3′,5′‐cyclic monophosphorothioate triethylammonium salt) and 2‐APB were purchased from Sigma‐Aldrich. N‐[(1R)‐1,2,3,4‐Tetrahydro‐1‐naphthalenyl]‐1H‐benzimidazol‐2‐amine hydrochloride (NS8593) was purchased from Tocris (Bristol, UK).…”

“…Prostaglandin E2 (PGE2), derived from arachidonic acid through the action of cyclooxygenase‐1/‐2 (COX‐1/‐2) and PGE2 synthase, is a potent endogenous lipid mediator . It is the most widely produced prostanoid in the human body .…”

“…Prostaglandin E2 (PGE2), derived from arachidonic acid through the action of cyclooxygenase-1/-2 (COX-1/-2) and PGE2 synthase, is a potent endogenous lipid mediator. 1 It is the most widely produced prostanoid in the human body. 2 PGE2 plays important roles in various pathological and physiological functions, such as cell proliferation, 3 apoptosis, 4 cancer, 5,6 inflammation, 7 hypertension, 8 Alzeheimer's disease, 9 diabetes 10,11 and immune response.…”