Cyclooxygenases and the cardiovascular system

Abstract

Cyclooxygenase (COX)-1 and COX-2 are centrally important enzymes within the cardiovascular system with a range of diverse, sometimes opposing, functions. Through the production of thromboxane, COX in platelets is a pro-thrombotic enzyme. By contrast, through the production of prostacyclin, COX in endothelial cells is antithrombotic and in the kidney regulates renal function and blood pressure. Drug inhibition of COX within the cardiovascular system is important for both therapeutic intervention with low dose aspirin and for the manifestation of side effects caused by nonsteroidal anti-inflammatory drugs. This review focuses on the role that COX enzymes and drugs that act on COX pathways have within the cardiovascular system and provides an in-depth resource covering COX biology and pharmacology. The review goes on to consider the role of COX in both discrete cardiovascular locations and in associated organs that contribute to cardiovascular health.We discuss the importance of, and strategies to manipulate, the thromboxane: prostacyclin balance.Finally within this review the authors discuss testable COX-2-hypotheses intended to stimulate debate and facilitate future research and therapeutic opportunities within the field.

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

“…Rofecoxib also completely prevented the hypotensive effects of the ACEi inhibitor lisinopril in SHRs (Ricciotti et al 2018 ; Dubey et al 2005 ). Most importantly, clinical studies suggest that hypertension was more common in patients taking COX-2 inhibitors such as celecoxib and etoricoxib, and COX inhibition may attenuate the effects of some antihypertensive therapeutics (Mitchell et al 2020 ; Chan et al 2009 ). Therefore, COX-2 has the ability to decrease blood pressure.…”

“…Coxibs not only attenuate pain and inflammation but also reduce the incidence of serious GI adverse effects. However, coxibs also cause cardiovascular hazards, including atherosclerosis (coronary heart disease), hypertension, myocardial infarction, stroke, heart failure, arrhythmogenesis and sudden cardiac death (Bahmani et al 2017 ; Mitchell et al 2020 ). Celecoxib was removed from the market in 2004 by the Food and Drug Administration (FDA).…”

A new insight into subinteractomes of functional antagonists: Thromboxane (CYP5A1) and prostacyclin (CYP8A1) synthases

“…So far, Spisni and colleagues have provided evidence of the formation of a protein complex between PTGIS and caveolin (CAV1) (Spisni et al, 2001). The indirect strategy to restore the normal ratio of thromboxane A 2 : prostacyclin lies in pharmacological exposure of low doses of aspirin and other non‐steroidal anti‐inflammatory drugs (NSAIDs), which inhibit cyclooxygenase‐1 (COX‐1) in the platelets and reduce this ratio (Mitchell et al, 2020). At the same time, both CYP5A1 and CYP8A1 as well as prostaglandin receptors are “druggable” proteins and are considered as molecular targets for the development of therapeutics for correction of the aberrant production of bioactive lipid mediators in the organism (Khan et al, 2020; Mesitskaya et al, 2018).…”

Cycle Network Model of Prostaglandin H Synthase-1

“…Prostaglandin H synthase-1 (PGHS-1), also known as Cyclooxygenase-1 (COX-1), catalyses the first stage in the conversion of arachidonic acid (AA) into prostaglandin H 2 (PGH 2 ), being a precursor of physiologically active prostanoids [ 1 ]. PGHS-1 and the other isoform of PGHS (PGHS-2) are the main targets of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of pain, fever, inflammation, and cardiovascular diseases [ 2 ]. Despite the fact that this enzyme has been under thorough investigation for several decades, some details of its catalytic mechanism are still not completely understood [ 3 ].…”