Hypoxia-inducible factor 1-induced G protein-coupled receptor 35 expression is an early marker of progressive cardiac remodelling

Ronkainen, Veli‐Pekka; Tuomainen, Tomi Pekka; Huusko, Jenni; Laidinen, Svetlana; Malinen, Marjo; Palvimo, Jorma J.; Ylä‐Herttuala, Seppo; Vuolteenaho, Olli; Tavi, Pasi

doi:10.1093/cvr/cvt226

Cited by 45 publications

(48 citation statements)

References 32 publications

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“…Interestingly, GPR35 is a HIF target that is induced during cardiac remodeling (Ronkainen et al, 2014). Clearly additional studies are required to determine how KYNA protects the heart.…”

Section: Discussionmentioning

confidence: 99%

EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection

Olenchock¹,

Moslehi²,

Baik³

et al. 2016

Cell

114

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SUMMARY Ischemic preconditioning is the phenomenon whereby brief periods of sublethal ischemia protect against a subsequent, more prolonged, ischemic insult. In remote ischemic preconditioning (RIPC), ischemia to one organ protects others organs at a distance. We created mouse models to ask if inhibition of the alpha-ketoglutarate (αKG)-dependent dioxygenase Egln1, which senses oxygen and regulates the HIF transcription factor, could suffice to mediate local and remote ischemic preconditioning. Using somatic gene deletion and a pharmacological inhibitor, we found that inhibiting Egln1 systemically or in skeletal muscles protects mice against myocardial ischemia-reperfusion (I/R) injury. Parabiosis experiments confirmed that RIPC in this latter model was mediated by a secreted factor. Egln1 loss causes accumulation of circulating αKG, which drives hepatic production and secretion of kynurenic acid (KYNA) that is necessary and sufficient to mediate cardiac ischemic protection in this setting.

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“…Interestingly, GPR35 is a HIF target that is induced during cardiac remodeling (Ronkainen et al, 2014). Clearly additional studies are required to determine how KYNA protects the heart.…”

Section: Discussionmentioning

confidence: 99%

EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection

Olenchock¹,

Moslehi²,

Baik³

et al. 2016

Cell

114

View full text Add to dashboard Cite

show abstract

“…Moreover, mice deficient in GPR35 have higher blood pressure than their wild-type littermates which further indicates a role for GPR35 in cardiovascular disease pathophysiology [137]. In accordance, GPR35 expression is upregulated in cardiac myocytes upon oxygen scarcity [133]. In agreement, GPR35 mRNA was found to be significantly upregulated in myocardial tissue of patients with chronic heart failure compared to healthy controls [137].…”

Section: Gpr35 Associations With Metabolic Diseasementioning

confidence: 76%

“…Alongside its initial discovery, GPR35 was shown to be expressed in the rat small intestine [130], and indeed, both human and murine GPR35 show predominant expression in the gastrointestinal (GI) tract. Other tissues displaying high GPR35 transcript levels include the brain, pancreas, spleen, immune cells, heart and adipocytes [131][132][133]. Considering its predominant expression in the GI tract, it is not unexpected that GPR35 has been linked to several GI pathologies.…”

Section: Gpr35 Associations With Metabolic Diseasementioning

confidence: 99%

The weight of nutrients: kynurenine metabolites in obesity and exercise

et al. 2018

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Obesity ultimately results from an imbalance between energy intake and expenditure. However, in addition to their bioenergetic value, nutrients and their metabolites can function as important signalling molecules in energy homeostasis. Indeed, macronutrients and their metabolites can be direct regulators of metabolism through their actions on different organs. In turn, target organs can decide to use, store or transform the incoming nutrients depending on their physiological context and in coordination with other cell types. Tryptophan-kynurenine metabolites are an example of a family of compounds that can serve as systemic integrators of energy metabolism by signalling to different cell types. These include adipocytes, immune cells and muscle fibres, in addition to the well-known effects of kynurenine metabolites on the central nervous system. In the context of energy metabolism, several of the effects elicited by kynurenic acid are mediated by the G-protein-coupled receptor, GPR35. As GPR35 is expressed in tissues such as the adipose tissue, immune cells and the gastrointestinal tract, this receptor could be a potential therapeutic target for the treatment of obesity, diabetes and other metabolic diseases. In addition, metabolic disorders often coincide with states of chronic inflammation, which further highlights GPR35 as an integration node in conditions where inflammation skews metabolism. Defining the molecular interplay between different tissues in the regulation of energy homeostasis can help us understand interindividual variability in the response to nutrient intake and develop safe and efficient therapies to fight obesity and metabolic disease.

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“…A more detailed investigation of GPR35 expression in neonatal mouse cardiomyocytes found both mRNA and cell surface protein levels to increase in response to hypoxia and hypoxia-inducible factor 1 activation ( Ronkainen et al, 2014 ). Considering that hypoxia is a feature of most chronic cardiac pathologies, this provides a possible rationale for the apparently broad involvement of GPR35 in cardiovascular disease.…”

Section: Gpr35 As a Therapeutic Targetmentioning

confidence: 99%

G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease

et al. 2015

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G protein-coupled receptor 35 (GPR35) is an orphan receptor, discovered in 1998, that has garnered interest as a potential therapeutic target through its association with a range of diseases. However, a lack of pharmacological tools and the absence of convincingly defined endogenous ligands have hampered the understanding of function necessary to exploit it therapeutically. Although several endogenous molecules can activate GPR35 none has yet been confirmed as the key endogenous ligand due to reasons that include lack of biological specificity, non-physiologically relevant potency and species ortholog selectivity. Recent advances have identified several highly potent synthetic agonists and antagonists, as well as agonists with equivalent potency at rodent and human orthologs, which will be useful as tool compounds. Homology modeling and mutagenesis studies have provided insight into the mode of ligand binding and possible reasons for the species selectivity of some ligands. Advances have also been made in determining the role of the receptor in disease. In the past, genome-wide association studies have associated GPR35 with diseases such as inflammatory bowel disease, type 2 diabetes, and coronary artery disease. More recent functional studies have implicated it in processes as diverse as heart failure and hypoxia, inflammation, pain transduction and synaptic transmission. In this review, we summarize the progress made in understanding the molecular pharmacology, downstream signaling and physiological function of GPR35, and discuss its emerging potential applications as a therapeutic target.

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Hypoxia-inducible factor 1-induced G protein-coupled receptor 35 expression is an early marker of progressive cardiac remodelling

Abstract: Cardiac expression of GPR35 is regulated by hypoxia through activation of HIF-1. The expression of GPR35 in mouse models of cardiac infarction and pressure load suggests that GPR35 could be used as an early marker of progressive cardiac failure.

Cited by 45 publications

References 32 publications

EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection

EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection

The weight of nutrients: kynurenine metabolites in obesity and exercise

G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease

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