Inhibition of GPR39 restores defects in endothelial cell-mediated neovascularization under the duress of chronic hyperglycemia: Evidence for regulatory roles of the sonic hedgehog signaling axis.
Inhibition of GPR39 restores defects in endothelial cell-mediated neovascularization under the duress of chronic hyperglycemia: Evidence for regulatory roles of the sonic hedgehog signaling axis.
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DOI：
10.1073/pnas.2208541120
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发表时间：
2023-01-03
影响因子：
11.1
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中科院分区：
文献类型：
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GPR 39是一种孤儿GPR，其在EC中的生理配体和细胞内途径仍然缺乏表征。我们的数据表明，抑制GPR 39通过增强主动脉EC中的SHH信号来保护EC功能。了解高血糖症中GPR 39激活和SHH信号传导之间的潜在串扰可能成为开发针对糖尿病患者心血管并发症的治疗方法的基础。我们的研究还显示，在2型糖尿病小鼠模型中，GPR 39的基因消融显著改善了体内缺血后的血管重建。我们的研究通过靶向GPR 39为保护内皮功能和血管健康开辟了一条途径。开发药物或基因制剂来阻断内皮细胞中的GPR 39可能是未来研究的一个富有成果的领域。内皮细胞介导的血管生成受损导致糖尿病患者严重肢体缺血。音刺猬（SHH）途径参与血管生成，但在高血糖症中受到抑制的模糊机制。我们研究了孤儿G蛋白偶联受体GPR 39对内皮细胞SHH通路激活和慢性高血糖动物缺血诱导的血管生成的影响。在体外培养来自健康和2型糖尿病（T2 D）供体的人主动脉EC。T2 D组GPR 39 mRNA表达显著升高。腺病毒介导的GPR 39过表达（Ad-GPR 39）或GPR 39激动剂TC-G-1008可抑制EC增殖、迁移和管腔形成。Ad-GPR 39可减少促血管生成因子的产生。相反，与其各自的对照相比，用GPR 39 siRNA转染的人EC或从GPR 39全基因敲除（GPR 39 KO）小鼠分离的小鼠主动脉EC显示增强的迁移和增殖。GPR 39抑制SHH效应物GLI 1的基础和配体依赖性激活，导致EC迁移减弱。免疫共沉淀显示，GPR 39与SHH通路内源性抑制剂融合抑制因子（SUFU）的直接结合可以实现这一点。此外，在GPR 39敲低的EC中，SUFU过表达消除了强烈的GLI 1激活和EC迁移。在饮食诱导的肥胖（DIO）和低剂量链脲佐菌素（STZ）诱导的高血糖症的慢性糖尿病模型中，GPR 39 KO小鼠表现出比GPR 39野生型（GPR 39 WT）对应物更快的后肢缺血血管重建速度和更低的组织坏死发生率。这些发现为开发治疗工具提供了概念框架，这些治疗工具在代谢应激下消融或抑制GPR 39用于缺血组织修复。
GPR39 is an orphan GPR whose physiological ligand and intracellular pathways in ECs remain poorly characterized. Our data indicate that inhibition of GPR39 protects EC functions by enhancing SHH signaling in aortic ECs. Understanding the potential cross-talk between GPR39 activation and SHH signaling in hyperglycemia may form the basis for developing therapeutic approaches to target cardiovascular complications in diabetic patients. Our studies also revealed that genetic ablation of GPR39 significantly improves revascularization after ischemia in vivo in a type 2 diabetic mouse model. Our studies open an avenue to preserving endothelial function and vascular health by targeting GPR39. The development of pharmacological or genetic agents to block GPR39 in ECs may be a fruitful area of future research. Impaired endothelial cell (EC)–mediated angiogenesis contributes to critical limb ischemia in diabetic patients. The sonic hedgehog (SHH) pathway participates in angiogenesis but is repressed in hyperglycemia by obscure mechanisms. We investigated the orphan G protein–coupled receptor GPR39 on SHH pathway activation in ECs and ischemia-induced angiogenesis in animals with chronic hyperglycemia. Human aortic ECs from healthy and type 2 diabetic (T2D) donors were cultured in vitro. GPR39 mRNA expression was significantly elevated in T2D. The EC proliferation, migration, and tube formation were attenuated by adenovirus-mediated GPR39 overexpression (Ad-GPR39) or GPR39 agonist TC-G-1008 in vitro. The production of proangiogenic factors was reduced by Ad-GPR39. Conversely, human ECs transfected with GPR39 siRNA or the mouse aortic ECs isolated from GPR39 global knockout (GPR39KO) mice displayed enhanced migration and proliferation compared with their respective controls. GPR39 suppressed the basal and ligand-dependent activation of the SHH effector GLI1, leading to attenuated EC migration. Coimmunoprecipitation revealed that the GPR39 direct binding of the suppressor of fused (SUFU), the SHH pathway endogenous inhibitor, may achieve this. Furthermore, in ECs with GPR39 knockdown, the robust GLI1 activation and EC migration were abolished by SUFU overexpression. In a chronic diabetic model of diet-induced obesity (DIO) and low-dose streptozotocin (STZ)-induced hyperglycemia, the GPR39KO mice demonstrated a faster pace of revascularization from hind limb ischemia and lower incidence of tissue necrosis than GPR39 wild-type (GPR39WT) counterparts. These findings have provided a conceptual framework for developing therapeutic tools that ablate or inhibit GPR39 for ischemic tissue repair under metabolic stress.
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影响因子：
2.7
作者：
Fernandes-Silva H;Correia-Pinto J;Moura RS
通讯作者：
Moura RS
影响因子：
2.7
作者：
Benjamini, Yoav;Krieger, Abba M.;Yekutieli, Daniel
通讯作者：
Yekutieli, Daniel
影响因子：
4.8
作者：
Holst, Birgitte;Egerod, Kristoffer L.;Schwartz, Thue W.
通讯作者：
Schwartz, Thue W.
DOI：
10.1073/pnas.0602956103
发表时间：
2006-06-13
影响因子：
11.1
作者：
Le May, Cedric;Chu, Khoi;Mauvais-Jarvis, Franck
通讯作者：
Mauvais-Jarvis, Franck
影响因子：
8.8
作者：
Di Mauro C;Rosa R;D'Amato V;Ciciola P;Servetto A;Marciano R;Orsini RC;Formisano L;De Falco S;Cicatiello V;Di Bonito M;Cantile M;Collina F;Chambery A;Veneziani BM;De Placido S;Bianco R
通讯作者：
Bianco R