Hypoxia-inducible factor 1-induced G protein-coupled receptor 35 expression is an early marker of progressive cardiac remodelling
Hypoxia-inducible factor 1-induced G protein-coupled receptor 35 expression is an early marker of progressive cardiac remodelling
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DOI：
10.1093/cvr/cvt226
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发表时间：
2014-01-01
影响因子：
10.8
通讯作者：
Tavi, Pasi
中科院分区：
文献类型：
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作者：
Ronkainen, Veli-Pekka;Tuomainen, Tomi;Tavi, Pasi
G蛋白偶联受体35（GPR 35）是心力衰竭中表达上调的基因之一。由于GPR 35表达的调控机制尚不清楚，我们研究了心肌细胞和心力衰竭小鼠模型中GPR 35基因和蛋白表达的调控，发现心肌细胞中GPR 35基因表达对缺氧异常敏感，并由缺氧诱导因子-1（HIF-1）激活诱导。HIF-1依赖性调节通过HIF-1途径的遗传（HIF-1/VP 16，抑制性Per/Arnt/Sim结构域蛋白）和化学[去铁胺（DFO）]调节建立，并通过GPR 35启动子的突变分析和证明内源性HIF-1与基因启动子的直接结合进一步证实。缺氧使心肌细胞膜GPR 35受体的数量和密度增加。化学GPR 35激动剂扎普司特引起心肌细胞中GPR 35活化和受体内化。此外，过表达GPR 35破坏了肌动蛋白细胞骨架的排列，并引起培养心肌细胞的形态学变化。GPR 35基因和蛋白的表达也在心力衰竭小鼠模型、心肌梗死急性期和压力负荷诱导的心脏肥大的代偿期和失代偿期被诱导。GPR 35在心肌梗死和压力负荷小鼠模型中的表达表明，GPR 35可用作进行性心力衰竭的早期标志物。
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.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.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.