Roles of prostanoids in the pathogenesis of cardiovascular diseases: Novel insights from knockout mouse studies

Yuhki, Koh Ichi; Kojima, Fumio; Kashiwagi, Hitoshi; Kawabe, Jun Ichi; Fujino, Takayuki; Narumiya, Shuh; Ushikubi, Fumitaka

doi:10.1016/j.pharmthera.2010.09.004

Cited by 105 publications

(92 citation statements)

References 163 publications

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“…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.…”

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confidence: 99%

Roles of Prostaglandin E2 in Cardiovascular Diseases

et al. 2011

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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...

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confidence: 99%

Roles of Prostaglandin E2 in Cardiovascular Diseases

et al. 2011

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“…Moreover, this is a characteristic of the prostanoid system in general, where the impact on blood pressure and hemodynamic functions is minimal in healthy individuals and only becomes apparent in the face of physiological stresses or disease. 25 On the other hand, we and others have shown that production of thromboxane is enhanced in models of hypertension caused by Ang II infusion or administration of N G -nitro-larginine methyl ester. 14,18,29 Moreover, blockade of TP signaling either through pharmacological inhibition or complete deletion of the TP receptor gene reduces the severity of hypertension in these models.…”

Section: Discussionmentioning

confidence: 93%

“…25 Activation of TP receptors by TxA 2 induces broad actions that could contribute to cardiovascular pathogenesis including vasoconstriction, platelet activation, oxidative stress, and promoting immune responses and inflammation. [26][27][28] In this study, we were interested in precisely defining the contribution of vascular actions of TP receptors to the regulation of blood pressure.…”

Section: Discussionmentioning

confidence: 99%

Thromboxane Receptors in Smooth Muscle Promote Hypertension, Vascular Remodeling, and Sudden Death

Sparks

Makhanova²,

Griffiths³

et al. 2013

Hypertension

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Abstract-The prostanoid thromboxane A 2 has been implicated to contribute to the pathogenesis of many cardiovascular diseases, including hypertension. To study the role of vascular thromboxane-prostanoid (TP) receptors in blood pressure regulation, we generated mice with cell-specific deletion of TP receptors in smooth muscle using Cre/Loxp technology. We crossed the KISM22α-Cre transgenic mouse line expressing Cre recombinase in smooth muscle cells with a mouse line bearing a conditional allele of the Tbxa2r gene (Tp flox ). In KISM22α-Cre + Tp flox/flox (TP-SMKO) mice, TP receptors were efficiently deleted from vascular smooth muscle cells. In TP-SMKOs, acute vasoconstrictor responses to the TP agonist U46619 were attenuated to a similar extent in both the peripheral and renal circulations. Yet, acute vascular responses to angiotensin II were unaffected at baseline and after chronic angiotensin II administration. Infusion of high-dose U46619 caused circulatory collapse and death in a majority of control mice but had negligible hemodynamic effects in TPSMKOs, which were completely protected from U46619-induced sudden death. Baseline blood pressures were normal in TP-SMKOs. However, the absence of TP receptors in vascular smooth muscle cells was associated with significant attenuation of angiotensin II-induced hypertension and diminished vascular remodeling. This was also associated with reduced urinary thromboxane production after chronic angiotensin II. Thus, TP receptors in vascular smooth muscle cells play a major role in mediating the actions of thromboxane A 2 in TP agonist-induced shock, hypertension, and vascular remodeling of the aorta.

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“…Isoprostanes are a class of prostaglandin-like products formed via free-radical-mediated oxidation of arachidonic acid, esterified in membrane phospholipids. All these lipid mediators are consistently observed in atherosclerotic lesions where, together with the oxLDL-derived oxidized lipids, they contribute to the inflammatory responses and to plaque progression [228][229][230][231][232].…”

Section: Arachidonic Acid Derivatives In Atherosclerosismentioning

confidence: 99%

“…Several lines of evidence suggest that isoprostane generation may reflect oxidative stress and inflammation in experimental and human atherosclerosis [230,259]. Moreover, isoprostanes are useful biomarkers of cardiovascular diseases [260].…”

Section: Isoprostanesmentioning

confidence: 99%