Identification of a Potent and Selective GPR4 Antagonist as a Drug Lead for the Treatment of Myocardial Infarction

Fukuda, Hayato; Ito, Saki; Watari, Kenji; Mogi, Chihiro; Arisawa, Mitsuhiro; Okajima, Fumikazu; Kurose, Hitoshi; Shuto, Satoshi

doi:10.1021/acsmedchemlett.6b00014

Cited by 47 publications

(65 citation statements)

References 10 publications

(22 reference statements)

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“…Other similar GPR4 inhibitors have also been shown to reduce acidosis-induced EC inflammation and promote survival in a mouse myocardial infarction model [21,23]. We aimed to use the GPR4 inhibitor (EIDIP) to study the acidosis-induced endothelial ER stress/UPR effects.…”

Section: Resultsmentioning

confidence: 99%

Acidosis Activates Endoplasmic Reticulum Stress Pathways through GPR4 in Human Vascular Endothelial Cells

Dong

Krewson

Yang

2017

IJMS

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Acidosis commonly exists in the tissue microenvironment of various pathophysiological conditions such as tumors, inflammation, ischemia, metabolic disease, and respiratory disease. For instance, the tumor microenvironment is characterized by acidosis and hypoxia due to tumor heterogeneity, aerobic glycolysis (the “Warburg effect”), and the defective vasculature that cannot efficiently deliver oxygen and nutrients or remove metabolic acid byproduct. How the acidic microenvironment affects the function of blood vessels, however, is not well defined. GPR4 (G protein-coupled receptor 4) is a member of the proton-sensing G protein-coupled receptors and it has high expression in endothelial cells (ECs). We have previously reported that acidosis induces a broad inflammatory response in ECs. Acidosis also increases the expression of several endoplasmic reticulum (ER) stress response genes such as CHOP (C/EBP homologous protein) and ATF3 (activating transcription factor 3). In the current study, we have examined acidosis/GPR4-induced ER stress pathways in human umbilical vein endothelial cells (HUVEC) and other types of ECs. All three arms of the ER stress/unfolded protein response (UPR) pathways were activated by acidosis in ECs as an increased expression of phosphorylated eIF2α (eukaryotic initiation factor 2α), phosphorylated IRE1α (inositol-requiring enzyme 1α), and cleaved ATF6 upon acidic pH treatment was observed. The expression of other downstream mediators of the UPR, such as ATF4, ATF3, and spliced XBP-1 (X box-binding protein 1), was also induced by acidosis. Through genetic and pharmacological approaches to modulate the expression level or activity of GPR4 in HUVEC, we found that GPR4 plays an important role in mediating the ER stress response induced by acidosis. As ER stress/UPR can cause inflammation and cell apoptosis, acidosis/GPR4-induced ER stress pathways in ECs may regulate vascular growth and inflammatory response in the acidic microenvironment.

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Section: Resultsmentioning

confidence: 99%

Acidosis Activates Endoplasmic Reticulum Stress Pathways through GPR4 in Human Vascular Endothelial Cells

Dong

Krewson

Yang

2017

IJMS

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“…Use of GPR4 inhibitors could prove as a valuable tool to inhibit inflammation by reducing leukocyte recruitment and adhesion to inflamed tissues. Recently, our group and others have demonstrated the effectiveness of the GPR4 inhibitors in the selective targeting of GPR4 and inhibition of GPR4 target gene expression [15, 17, 73]. Additionally, GPR4 antagonists have been used in vivo and no obvious toxicities have been reported [18, 73].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, our group and others have demonstrated the effectiveness of the GPR4 inhibitors in the selective targeting of GPR4 and inhibition of GPR4 target gene expression [15, 17, 73]. Additionally, GPR4 antagonists have been used in vivo and no obvious toxicities have been reported [18, 73]. A recent study showed that GPR4 antagonists provided therapeutic benefits in a myocardial infarction mouse model [73].…”

Section: Discussionmentioning

confidence: 99%

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GPR4 deficiency alleviates intestinal inflammation in a mouse model of acute experimental colitis

Sanderlin

Leffler

Lertpiriyapong

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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GPR4 is a proton-sensing G protein-coupled receptor that can be activated by extracellular acidosis. It has recently been demonstrated that activation of GPR4 by acidosis increases the expression of numerous inflammatory and stress response genes in vascular endothelial cells (ECs) and also augments EC-leukocyte adhesion. Inhibition of GPR4 by siRNA or small molecule inhibitors reduces endothelial cell inflammation. As acidotic tissue microenvironments exist in many types of inflammatory disorders, including inflammatory bowel disease (IBD), we examined the role of GPR4 in intestinal inflammation using a dextran sulfate sodium (DSS)-induced acute colitis mouse model. We observed that GPR4 mRNA expression was increased in mouse and human IBD tissues when compared to control intestinal tissues. To determine the function of GPR4 in intestinal inflammation, wild-type and GPR4-deficient mice were treated with 3% DSS for 7 days to induce acute colitis. Our results showed that the severity of colitis was decreased in GPR4-deficient DSS-treated mice in comparison to wild-type DSS-treated mice. Clinical parameters, macroscopic disease indicators, and histopathological features were less severe in the DSS-treated GPR4-deficient mice than the DSS-treated wild-type mice. Endothelial adhesion molecule expression, leukocyte infiltration, and isolated lymphoid follicle (ILF) formation were reduced in intestinal tissues of DSS-treated GPR4-null mice. Collectively, our results suggest GPR4 provides a pro-inflammatory role in the inflamed gut as the absence of GPR4 ameliorates intestinal inflammation in the acute experimental colitis mouse model.

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“…GPR4 inhibitors have proved effective in the reduction of endothelial inflammation and subsequent tissue inflammation in vitro and in vivo Dong et al, 2013;Fukuda et al, 2016;Hosford et al, 2018;Miltz et al, 2017;Tobo et al, 2015;Velcicky et al, 2017). A group of imidazo-pyridine and pyrazolopyrimidine derivatives were previously found to elicit inhibitory effects on GPR4-mediated EC activation Dong et al, 2013;Hosford et al, 2018;Miltz et al, 2017;Tobo et al, 2015;Velcicky et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of GPR4 remediates intestinal inflammation in a mouse colitis model

Sanderlin

Marie

Velcicky

et al. 2019

Preprint

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Inflammatory bowel disease (IBD) is characterized by chronic, recurring inflammation of the digestive tract. Current therapeutic approaches are limited and include biologics and steroids such as anti-TNFα monoclonal antibodies and corticosteroids, respectively. Significant adverse drug effects can occur for chronic usage and include increased risk of infection in some patients. GPR4, a pH-sensing G protein-coupled receptor, has recently emerged as a potential therapeutic target for intestinal inflammation. We have assessed the effects of a GPR4 antagonist, 2-(4-((2-Ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)phenyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (GPR4 antagonist 13, also known as NE 52-QQ57) in the dextran sulfate sodium (DSS)-induced acute colitis mouse model. The GPR4 antagonist 13 inhibited intestinal inflammation. The clinical parameters such as body weight loss and fecal score were reduced in the GPR4 antagonist 13 treatment group compared to vehicle control.Macroscopic disease indicators such as colon shortening, splenic expansion, and mesenteric lymph node enlargement were all reduced in severity in the GPR4 antagonist 13 treated mice.Histopathological features of active colitis were alleviated in GPR4 antagonist 13 treatment groups compared to vehicle control. Finally, inflammatory gene expression in the colon tissues and vascular adhesion molecule expression in the intestinal endothelia were attenuated by GPR4 antagonist 13. Our results indicate that GPR4 antagonist 13 provides a protective effect in the DSS-induced acute colitis mouse model, and inhibition of GPR4 can be explored as a novel anti-inflammatory approach.

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Identification of a Potent and Selective GPR4 Antagonist as a Drug Lead for the Treatment of Myocardial Infarction

Cited by 47 publications

References 10 publications

Acidosis Activates Endoplasmic Reticulum Stress Pathways through GPR4 in Human Vascular Endothelial Cells

Acidosis Activates Endoplasmic Reticulum Stress Pathways through GPR4 in Human Vascular Endothelial Cells

GPR4 deficiency alleviates intestinal inflammation in a mouse model of acute experimental colitis

Pharmacological inhibition of GPR4 remediates intestinal inflammation in a mouse colitis model

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