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

Abstract

AIMS:

G protein-coupled receptor 35 (GPR35) has been characterized to be one of the genes that are up-regulated in human heart failure. Since mechanisms controlling GPR35 expression are not known, we investigated the regulation of GPR35 gene and protein expression in cardiac myocytes and in the mouse models of cardiac failure.

METHODS AND RESULTS:

In cardiac myocytes, GPR35 gene expression was found to be exceptionally sensitive to hypoxia and induced by hypoxia-inducible factor-1 (HIF-1) activation. HIF-1-dependent regulation was established by genetic (HIF-1/VP16, Inhibitory Per/Arnt/Sim domain protein) and chemical [desferrioxamine (DFO)] modulation of the HIF-1 pathway and further confirmed by mutation analysis of the GPR35 promoter and by demonstrating direct binding of endogenous HIF-1 to the gene promoter. Hypoxia increased the number and density of GPR35 receptors on the cardiomyocyte cell membranes. Chemical GPR35 agonist Zaprinast caused GPR35 activation and receptor internalization in cardiac myocytes. In addition, overexpressed GPR35 disrupted actin cytoskeleton arrangement and caused morphological changes in cultured cardiomyocytes. GPR35 gene and protein expressions were also induced in mouse models of cardiac failure; the acute phase of myocardial infarction and during the compensatory and decompensatory phase of pressure-load induced cardiac hypertrophy.

CONCLUSIONS:

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.

• Authors: Veli-Pekka Ronkainen, Tomi Tuomainen, Jenni Huusko, Svetlana Laidinen, Marjo Malinen, Jorma J Palvimo, Seppo Ylä-Herttuala, Olli Vuolteenaho, Pasi Tavi
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 101 Issue 1 Pg. 69-77 (Jan 01 2014) ISSN: 1755-3245 [Electronic] England
• PMID: 24095869 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GPR35 protein, mouse
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Ligands
• Receptors, G-Protein-Coupled
• Oxygen

Topics

• Animals
• Animals, Newborn
• Cells, Cultured
• Gene Expression Regulation
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Ligands
• Male
• Mice
• Mice, Inbred C57BL
• Myocytes, Cardiac (metabolism)
• Oxygen (physiology)
• Promoter Regions, Genetic
• Receptors, G-Protein-Coupled (metabolism)
• Ventricular Remodeling