What role does Prostaglandin E2 play in cardiovascular disease?

What are Prostaglandins?

Prostaglandins (PG) are potent biologic substances produced by nearly all cells of the body in response to cell membrane injury. PGs are endogenous lipid autocoids which belongs to the family of Eicosanoids. Eicosanoids include prostaglandins, leukotrienes, and thromboxanes, which are derived from 20-carbon polyunsaturated fatty acid, affect a wide variety of cellular processes, including cell proliferation, differentiation, and apoptosis. Prostaglandins play a key role in inflammatory response and their synthesis is generally very low in uninflamed tissues, but increases immediately in acute inflammation prior to the recruitment of leukocytes and the infiltration of immune cells. In human vascular tissue, PGE₂ is involved in many physiological processes, such as increasing vascular permeability, cell proliferation, cell migration and control of vascular smooth muscle tone. There are four principal bioactive prostaglandins synthesized in vivo. Prostaglandin E₂ (PGE₂), prostacyclin (PGI₂), prostaglandin D₂ (PGD₂) and prostaglandin F_2α (PGF_2α).

Biosynthesis of Prostaglandins

Prostaglandins and thromboxane A₂ (TXA₂) are synthesized by a sequential series of three enzymatic reactions.

1. Arachidonic acid is released from the plasma membrane by phospholipases A₂ (PLAs). There are many isoforms of PLAs and these are of particular interest in cardiovascular biology given their role inflammatory processes and serve as useful biomarkers of inflammation. For instance, group IIA PLA2 is a secreted enzyme that has been identified as an acute phase protein with a role in the inflammatory response.
   
   
2. Following arachidonic acid release, a metabolic cascade is initiated by the prostaglandin G/H synthases or cyclooxygenases (COX) by converting arachidonic first to PGH2. This enzyme exists as distinct isoforms referred to as COX-1 and COX-2. COX-1 is expressed constitutively in most cells. COX-2 is induced by inflammatory stimuli, hormones and growth factors. Both enzymes contribute to the generation of prostaglandins. The two cyclooxygenase isoforms, COX-1 and COX-2 , are targets of nonsteroidal anti-inflammatory drugs (NSAIDs) such as acetaminophen, aspirin and indomethacin. These drugs have been traditionally used worldwide as analgesics. Studies in the early 1990s indicated that the inducible COX-2 was largely responsible for prostaglandin formation associated with inflammation, while COX-1 was important for prostaglandins of housekeeping function. Selective COX-2 inhibitors aimed to provide anti-inflammatory effect led to the development of two drugs in the early 90s. However, these drugs were withdrawn from the market due to adverse side effects. Therefore, there is a need for new therapeutics that would block COX-2–mediated inflammation while averting the associated cardiovascular risk.
   
   
3. PGE2 is synthesized from PGH2 by microsomal prostaglandin E synthases- (mPGES) 1 and mPGES-2 and cytosolic PGE₂ synthases (cPGES). cPGES is constitutively and abundantly expressed in the cytosol of various tissues and cells and it requires glutathione (GSH) as a cofactor. After PGE2 is formed, it is actively transported through the membrane and released outside the cells to exert their actions.

We offer a variety of immunoassays for the quantitative determination of PGE2. Our PGE2 ELISA kit is a competitive immunoassay for the quantitative determination of Prostaglandin E2 in biological fluids. Highly sensitive measurement, detecting as little as 13.4 pg/ml PGE2. We also offer a PGE₂ high sensitivity ELISA kit that is ultrasensitive, detecting as little as 8.26 pg/ml PGE₂. Additionally, our PGE₂ CLIA kit uses chemiluminescent detection.

Prostaglandin Receptors

Prostaglandins exert their diverse effects by activating rhodopsin-like seven transmembrane spanning G protein-coupled receptors. PGE₂ employ specific subtypes of prostaglandin E receptors (EPs), designated as EP1, EP2, EP3, and EP4 encoded by different genes called EPs: EP₁, EP₂, EP₃, and EP₄, that have unique signaling pathways. For example, EP1 couples to Gq and increases intracellular Ca²⁺. EP3 couples to Gi and inhibits the increase of cAMP. EP2 and EP4 receptors are coupled to Gs and signal by intracellular cAMP. EP1 and EP3 receptors are vasoconstructive and EP2/EP4 receptors are vasodilative. The EP4 receptor is the most widely distributed subtype which exists in almost all tissues, such as the heart, adipose tissue, skeletal muscle, and lung and is involved in various pathophysiological processes. Activation of PGE₂-EP4 signaling also can exert multiple biochemical effects on the heart, suggesting the potential wide-ranging use of EP4 in both cardiovascular and metabolic disorders.

Roles of PGE2 in Blood Pressure (BP) Regulation and Inflammation

PGE2 plays a diverse role in BP regulation depending on the site of action. PGE2 is a potent vasodilator, although in some circumstances, it can be a vasoconstrictor. In arteries for coronary bypass graft surgery, PGE2 induces vasoconstricition through EP3 receptors, suggesting that EP3 antagonists would offer a new therapeutic intervention to increase vascular graft patency. PGE2 is one of the most abundant PGs produced in the body, is most widely characterized in animal species, and exhibits versatile biological activities. Cellular mediators, such as cytokines and PGE₂, are produced by both immune/inflammatory and constitutive cells. Vascular cells, such as fibroblasts, endothelial and SMCs, are also involved in the basal synthesis of PGE₂. PGE2-mediated inflammation involves arterial dilatation and increased microvascular permeability. During the inflammatory response, the inflammatory mediators activate the transcription of target genes such as COX-2 and mPGES-1 and regulate PGE2 synthesis by activating the NF-κB pathway. These observations provide argument in a favor of a pro-inflammatory role of PGE₂ and it could be a target in anti-inflammatory therapy.

Role of PGE2 in Arterial Aneurysms

Arterial aneurysms (AA) are characterized by abnormal dilatation of the artery leading to vascular wall remodeling, weakening and rupture. A large number of inflammatory mediators such as cytokines and PGE₂ are observed to be associated at the site of rupture. Several studies have shown that PGE₂, TxA₂, and IL-6 secretions were significantly higher in human cultured explants of ruptured AA in comparison with non-ruptured AAA. The identification of biomarkers such as PGE₂ associated with the development of AA may suggest possible targets for new treatments to reduce AA progression. These results demonstrate the importance of PGE₂ as an inflammatory mediator and a putative biomarker in AA expansion, leading to the potential use of COX inhibitors as drugs to prevent or attenuate the risk of AA rupture.

Cardiac Transplantation

Cardiac rejection is a major complication in heart transplantation where cytokines and chemokines play critical roles in rejection. Expression of PGE2 and EPs play a critical role in its progression. Administration of Dimethyl analogue of PGE2 prolonged the survival of rat cardiac grafts. Research with EP2 and EP4 agonists prolonged cardiac allografts in cell culture systems. Thromboxane and PGs are frequently measured bioactive lipid markers in cardiovascular clinical studies. While many targets in the eicosanoid pathway are undergoing preclinical evaluation, further investigations on the role of PGE2 signaling pathways would aid in the development of better therapeutics to treat cardiovascular diseases.

Biomarker	Product	Targets for drug discovery
TxB2	TXB2 ELISA kit	Agonist platelet activation
11-dehydro-TXB2	11-dehydro-TXB2 ELISA kit	Platelet activation
12(S)-hydroperoxy tetraenoic eicosatetraenoic acid (HETE)	12(S)-HETE ELISA kit	Neutrophil recruitment
6-keto-PGF1α	6-keto-PGF1α ELISA kit	Platelet aggregation
COX-1	COX activity kit	Marker for inflammation and anti-inflammatory drug target

Table 1: Role of Prostanoids in Vascular pathologies.

A common assay is measuring blood cholesterol levels because lipid deposits on the arterial walls are a common cause of cardiovascular dysfunction. A complete lipid panel will measure the high-density lipoprotein (HDL), or “good” cholesterol, the low-density lipoprotein (LDL), or “bad” cholesterol, the overall total cholesterol, and triglycerides in the blood. These are usually done after an overnight fast for most accurate results. Healthy cholesterol levels are <200 mg/dL (Total), <130 mg/dL (LDL), and >40(men) or >50 (women) mg/dL (HDL), with <150 mg/dL good for triglycerides. Patients with undesirable cholesterol levels will be recommended healthy lifestyle changes and/or prescription of a cholesterol-lowering statin drug.

Enzo Life Sciences offers an extensive range of ready-to-use ELISA kits for a variety of research fields. We offer SCREEN-WELL® Cardiotoxicity Library, which is a focused collection of 130 compounds with defined and diverse cardiotoxicity, including ion channel blockage, mitochondrial toxicity and arrhythmia. The library compounds are used in screening and identifying novel candidates that would modulate cardiovascular signaling pathways and also serve as an essential tool for predictive toxicology screening and assay development. Our kits are well renowned and highly cited. Enzo Life Sciences has decades of experience developing and optimizing commercial immunoassays to meet the ever-changing needs of our scientific community. We provide a broad range of immunoassay kits reagents, biochemical assays and other research reagents for cardiovascular, immunology, cancer, neuroscience and other research fields, as well as industrial applications such as bioprocess monitoring. For more information on assay validation please download our ELISA E-book or contact our Technical Support Team for further assistance.

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