CXCR7 ameliorates myocardial infarction as a β-arrestin-biased receptor.
CXCR7 ameliorates myocardial infarction as a β-arrestin-biased receptor.
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DOI：
10.1038/s41598-021-83022-5
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发表时间：
2021-02-09
影响因子：
4.6
通讯作者：
Komuro I
中科院分区：
文献类型：
--
作者：
Ishizuka M;Harada M;Nomura S;Ko T;Ikeda Y;Guo J;Bujo S;Yanagisawa-Murakami H;Satoh M;Yamada S;Kumagai H;Motozawa Y;Hara H;Fujiwara T;Sato T;Takeda N;Takeda N;Otsu K;Morita H;Toko H;Komuro I
大多数七跨膜受体（7 TMR）是G蛋白偶联受体;然而，一些7 TMR通过β-抑制蛋白作为偏向性受体来诱发细胞内信号。由于已经报道了几种β-抑制蛋白偏向性激动剂具有心脏保护作用，我们研究了趋化因子受体CXCR 7作为心脏中的β-抑制蛋白偏向性受体的作用。在检测的510个7 TMR基因中，Cxcr 7在小鼠心脏中表达最丰富。单细胞RNA测序分析显示，Cxcr 7在心肌细胞和成纤维细胞中大量表达。心肌细胞特异性Cxcr 7基因敲除小鼠在心肌梗死后4周表现出比对照小鼠更显著的心脏扩张和功能障碍。相比之下，即使在心肌梗死后，成纤维细胞特异性Cxcr 7基因敲除小鼠和对照小鼠之间的心脏表型也没有差异。TC 14012是CXCR 7的特异性激动剂，在表达CXCR 7的细胞中显著募集β-arrestin至CXCR 7，并在新生大鼠心肌细胞中激活细胞外信号调节激酶（ERK）。对照组小鼠心脏边缘区Cxcr 7表达显著增加，ERK被激活，但Cxcr 7基因敲除小鼠则没有。这些结果表明，心肌细胞中大量表达的CXCR 7可能作为β-arrestin偏向性受体在心脏中发挥保护作用，CXCR 7可能成为心肌梗死治疗的新靶点。
Most seven transmembrane receptors (7TMRs) are G protein-coupled receptors; however, some 7TMRs evoke intracellular signals through β-arrestin as a biased receptor. As several β-arrestin-biased agonists have been reported to be cardioprotective, we examined the role of the chemokine receptor CXCR7 as a β-arrestin-biased receptor in the heart. Among 510 7TMR genes examined, Cxcr7 was the most abundantly expressed in the murine heart. Single-cell RNA-sequencing analysis revealed that Cxcr7 was abundantly expressed in cardiomyocytes and fibroblasts. Cardiomyocyte-specific Cxcr7 null mice showed more prominent cardiac dilatation and dysfunction than control mice 4 weeks after myocardial infarction. In contrast, there was no difference in cardiac phenotypes between fibroblast-specific Cxcr7-knockout mice and control mice even after myocardial infarction. TC14012, a specific agonist of CXCR7, significantly recruited β-arrestin to CXCR7 in CXCR7-expressing cells and activated extracellular signal-regulated kinase (ERK) in neonatal rat cardiomyocytes. Cxcr7 expression was significantly increased and ERK was activated in the border zone of the heart in control, but not Cxcr7 null mice. These results indicate that the abundantly expressed CXCR7 in cardiomyocytes may play a protective role in the heart as a β-arrestin-biased receptor and that CXCR7 may be a novel therapeutic target for myocardial infarction.
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影响因子：
16.6
作者：
Accornero F;Schips TG;Petrosino JM;Gu SQ;Kanisicak O;van Berlo JH;Molkentin JD
通讯作者：
Molkentin JD
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影响因子：
3
作者：
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通讯作者：
Horvath S
影响因子：
11.4
作者：
Bueno, OF;De Windt, LJ;Molkentin, JD
通讯作者：
Molkentin, JD
影响因子：
8.3
作者：
Galandrin, Segolene;Denis, Colette;Gales, Celine
通讯作者：
Gales, Celine
影响因子：
16.6
作者：
Beautrait A;Paradis JS;Zimmerman B;Giubilaro J;Nikolajev L;Armando S;Kobayashi H;Yamani L;Namkung Y;Heydenreich FM;Khoury E;Audet M;Roux PP;Veprintsev DB;Laporte SA;Bouvier M
通讯作者：
Bouvier M