Cardiovascular Biology of Prostanoids and Drug Discovery

Abstract

Prostanoids are a group of bioactive lipids that are synthesized de novo from membrane phospholipid-released arachidonic acid and have diverse functions in normal physiology and disease. NSAIDs (non-steroidal anti-inflammatory drugs), which are among the most commonly used medications, ameliorate pain, fever, and inflammation by inhibiting COX (cyclooxygenase), which is the rate-limiting enzyme in the biosynthetic cascade of prostanoids. The use of NSAIDs selective for COX-2 inhibition increases the risk of a thrombotic event (eg, myocardial infarction and stroke). All NSAIDs are associated with an increased risk of heart failure. Substantial variation in clinical responses to aspirin exists and is associated with cardiovascular risk. Limited clinical studies suggest the involvement of prostanoids in vascular restenosis in patients who received angioplasty intervention. mPGES (microsomal PG [prostaglandin] E synthase)-1, an alternative target downstream of COX, has the potential to be therapeutically targeted for inflammatory disease, with diminished thrombotic risk relative to selective COX-2 inhibitors. mPGES-1–derived PGE 2 critically regulates microcirculation via its receptor EP (receptor for prostanoid E) 4. This review summarizes the actions and associated mechanisms for modulating the biosynthesis of prostanoids in thrombosis, vascular remodeling, and ischemic heart disease as well as their therapeutic relevance.

A Pilot Metabolomic Study on Myocardial Injury Caused by Chronic Alcohol Consumption—Alcoholic Cardiomyopathy

“…Furthermore, DPA has been widely demonstrated to contribute to inhibition of platelet activation, anti-inflammatory effects, blood lipid improvement, and cardiovascular protective effects [14][15][16][17]. Conversely, prostaglandins, metabolites of arachidonic acid, have been widely proven to have proinflammatory effects [18]. Elevated levels of prostaglandin K1 (FC = 1.508, p = 0.005, VIP = 1.406) and K2 (FC = 6.798, p = 0.000, VIP = 2.021) were found in the present study, indicating proinflammatory effects on the myocardium caused by chronic alcohol consumption.…”

New horizons in the roles and associations of COX-2 and novel natural inhibitors in cardiovascular diseases

“…The systolic blood pressure was elevated in response to the selective inhibition (celecoxib), knockout, or mutation of COX-2 in mice with a mixed C57BL/6 × 129/Sv genetic background fed a regular chow diet (Cheng et al 2006 ). In addition, a specific COX-2 pharmacological inhibitor could increase blood pressure (Zhu et al 2020 ; Yao et al 2019 ). Celecoxib also significantly elevated blood pressure in both normal and hypertensive rats (Huang et al 2019 ).…”

“…Early reperfusion is helpful for myocardial salvage but easily induces reperfusion injury, which then reduces the benefits of myocardial reperfusion. Epidemiological studies have clearly established that COX-2 alleviates myocardial ischemia–reperfusion (I/R) injury (Zhu et al 2020 ; Bolli et al 2002 ). Endothelial COX-2–derived PGI2 suppresses platelet aggregation.…”

“…Celecoxib was removed from the market in 2004 by the Food and Drug Administration (FDA). The labels of COX-2 drugs must carry a “black box” warning to highlight the risks of serious cardiovascular events in many countries, including in the United States (US) and according to the Australian and European authorities related to the Therapeutic Goods Administration (TGA) (Arora et al 2020 ; Zhu et al 2020 ). Previous findings suggest that COX-2 may be a beneficial protein in the cardiovascular system.…”

LeMeDISCO: A computational method for large-scale prediction & molecular interpretation of disease comorbidity

“…COX are involved in the synthesis of prostanoids. Prostanoids are structurally like lipids and are involved in thrombosis and other undesirable cardiovascular events 20 . CAD is also known to be comorbid with proteinuria, Alport syndrome, glomerulonephritis, liver disease and mitral valve insufficiency.…”