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.
Highlights
Prostaglandin (PG) E2 is an important lipid mediator that regulates diverse and important physiological processes, such as gastric epithelial cytoprotection, renal blood flow maintenance, cardiovascular tone and blood pressure regulation, reproduction and parturition, bone formation, sleep, and neuroprotection
COX-1 is usually constitutively expressed in most tissues and responsible for the basal production of prostaglandin E2 (PGE2) that is involved in homeostasis of various physiological functions, such as gastrointestinal and kidney maintenance
These results suggest a dual involvement of the EP3 subtype in both cardioprotection and hypertrophy, which might be attributable to the expression diversity of EP3 isoforms in heart tissue
Summary
Prostaglandin (PG) E2 is an important lipid mediator that regulates diverse and important physiological processes, such as gastric epithelial cytoprotection, renal blood flow maintenance, cardiovascular tone and blood pressure regulation, reproduction and parturition, bone formation, sleep, and neuroprotection. One of the major pathophysiological functions of PGE2 is to elicit actions such as pyrexia, pain sensation, and inflammation. The analgesic and anesthetic effects of the most widely used nonsteroidal antiinflammatory drugs (NSAIDs) are thought to be driven by inhibition of the production of PGE2. COX-1 is usually constitutively expressed in most tissues and responsible for the basal production of PGE2 that is involved in homeostasis of various physiological functions, such as gastrointestinal and kidney maintenance. Its role in the production of inflammatory PGE2 and probably prostacyclin (PGI2) provided the rationale for the development of COX-2 selective NSAIDs, such as celecoxib, rofecoxib, and valdecoxib, for the management of pyrexia, relief of pain, and alleviation of inflammation with less gastrointestinal side effects [2]. Placebo-controlled trials revealed that these drugs predisposed patients to a series of cardiovascular hazards, including hypertension, stroke, myocardial infarction, heart failure, and sudden cardiac death, affecting ∼1-2% of patients exposed per year [3]
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