Roles of Prostaglandin E2 in Cardiovascular Diseases

Abstract

SummaryProstaglandin E2 (PGE 2 ) is produced in inflammatory responses and regulates a variety of immunological reactions through 4 different receptor subtypes; EP1, 2, 3 and 4. However, the precise role of each receptor in cardiovascular disease has not yet been elucidated. Enhanced expression of some EPs has been observed in clinical and experimental cardiovascular diseases. EP agonists have been developed to clarify the role of each receptor. Recently, we developed a novel selective agonist to examine the effects of EP4 on cardiac transplantation, myocardial ischemia, and myocarditis. Of note, a selective EP4 agonist attenuated inflammatory cytokines and chemokines via attenuation of macrophage activation in inflammatory heart diseases. In this review article, we discuss the effects of PGE 2 receptor agonists on the development of cardiovascular diseases. (Int Heart J 2011; 52: 266-269) Key words: Prostaglandin, Receptors, Chemokine, Macrophage, Heart P rostanoids are known to be multifunctional physiologic factors. They are produced by various stimuli and participate in local homeostasis and physiologic responses. They are synthesized from arachidonic acid and quickly released to the extracellular medium to send signals via prostanoid receptors.1) The prostanoid receptors, DP, EP, FP, IP and TP, are bound to PGD 2 , PGE 2 , PGF 2α , PGI 2 , and TXA 2 , respectively. 2)In the cardiovascular system, these receptors are expressed on various cells, such as cardiomyocytes, vascular endothelium and smooth muscle cells.3) They play an important role in modulating homeostasis in the development of cardiovascular diseases, such as thrombosis and atherosclerosis.4) Recent studies revealed that prostanoids play an important role in both the occurrence and suppression of various cardiovascular diseases, such as myocardial ischemia, cardiac hypertrophy, cardiac fibrosis, and atherosclerosis. 5) However, the detailed roles of prostanoids in cardiovascular disease have not yet been completely elucidated. To clarify the mechanisms, selective receptor agonists have been developed.Among the prostanoids, PGE 2 is known to play a key role in the pathogenesis of cardiovascular diseases. It was reported that a deficiency of PGE 2 synthase-1 reduced plaque burden in fat-diet low-density lipoprotein receptor knockout mice.6) Another report revealed that PGE 2 synthase-1 knockout mice showed impaired left ventricular contraction after acute myocardial infarction.7) These studies indicate that PGE 2 plays a pivotal role in cardiovascular inflammation. 8, 9) PGE 2 exerts their effects via G-protein-coupled receptors, and PGE 2 -mediated cardioprotection is involved in the EP receptor subtypes. 10)Each receptor has their unique signaling pathways. EP1 couples to Gq and increases intracellular Ca . EP3 couples to Gi and inhibits the increase of cAMP. EP2 and EP4 receptors are coupled to stimulate adenylate cyclase, which leads to the elevation of intracellular cAMP.11) In these EP receptors, EP3 and EP4 are known to have cardioprote...

An EP4 Receptor Agonist Inhibits Cardiac Fibrosis Through Activation of PKA Signaling in Hypertrophied Heart

“…PGE2 has been shown to play important roles in inflammation-based cardiovascular diseases such as myocardial ischemia, myocarditis, and rejection after cardiac transplantation, and the effects of EP4 agonists have been studied in the setting of these diseases. 20) This is the first study to describe the antifibrotic effects of ONO-0260164 in pressure overloadinduced cardiac remodeling.…”

Myeloid cell microsomal prostaglandin E synthase-1 fosters atherogenesis in mice

“…Finally, the consequences of PGE 2 suppression might differ between cell types. PGE 2 activates four E prostanoid (EP) receptors with contrasting intracellular signaling and consequent biology (15,16). Indeed, the contrasting effect of mPGES-1 deletion in myeloid vs. vascular cells on the proliferative response to vascular injury reflects the differential consequences of EP activation rather than substrate rediversion (8).…”

Prostaglandin E2 Signaling as a Target of Anti-Cardiac Fibrosis in Heart Failure Treatment

“…Kach, et al reported that noscapine, an antitussive drug, acts on lung fibroblasts and reduces fibrosis by inhibiting the TGF-β1 pathway via PKA activation. 12) With regard to cardiac disease, PGs have been mainly investigated in terms of their roles in inflammatory cell infiltration in the settings of myocardial ischemia, cardiac transplantation, and myocarditis, 9) and the roles of PGs in cardiac fibrosis have been less investigated. Wang, et al shed light on the importance of EP4-mediated anti-fibrotic effects in a murine heart failure model and partially revealed the molecular mechanisms in which PKA plays a central role in inhibiting the TGF-β1 pathway to treat cardiac fibrosis (Figure).…”