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Inositol-Requiring Enzyme 1 Facilitates Diabetic Wound Healing Through Modulating MicroRNAs

机译:需要肌醇的酶1通过调节MicroRNA促进糖尿病伤口的愈合。

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摘要

Diabetic skin ulcers represent a challenging clinical problem with mechanisms not fully understood. In this study, we investigated the role and mechanism for the primary unfolded protein response (UPR) transducer inositol-requiring enzyme 1 (IRE1α) in diabetic wound healing. Bone marrow-derived progenitor cells (BMPCs) were isolated from adult male type 2 diabetic and their littermate control mice. In diabetic BMPCs, IRE1α protein expression and phosphorylation were repressed. The impaired diabetic BMPC angiogenic function was rescued by adenovirus-mediated expression of IRE1α but not by the RNase-inactive IRE1α or the activated X-box binding protein 1 (XBP1), the canonical IRE1α target. In fact, IRE1α RNase processes a subset of micro-RNAs (miRs), including miR-466 and miR-200 families, through which IRE1α plays an important role in maintaining BMPC function under the diabetic condition. IRE1α attenuated maturation of miR-466 and miR-200 family members at precursor miR levels through the regulated IRE1α-dependent decay (RIDD) independent of XBP1. IRE1α deficiency in diabetes resulted in a burst of functional miRs from miR-466 and miR-200 families, which directly target and repress the mRNA encoding the angiogenic factor angiopoietin 1 (ANGPT1), leading to decreased ANGPT1 expression and disrupted angiogenesis. Importantly, cell therapies using IRE1α-expressing BMPCs or direct IRE1α gene transfer significantly accelerated cutaneous wound healing in diabetic mice through facilitating angiogenesis. In conclusion, our studies revealed a novel mechanistic basis for rescuing angiogenesis and tissue repair in diabetic wound treatments.
机译:糖尿病性皮肤溃疡代表了具有挑战性的临床问题,其机理尚不完全清楚。在这项研究中,我们调查了主要的未折叠蛋白应答(UPR)换能肌醇需要酶1(IRE1α)在糖尿病伤口愈合中的作用和机制。从成年雄性2型糖尿病小鼠及其同窝对照小鼠中分离出骨髓来源的祖细胞(BMPC)。在糖尿病BMPC中,IRE1α蛋白的表达和磷酸化受到抑制。受损的BMPC血管生成功能可通过腺病毒介导的IRE1α挽救,但不能通过RNase失活的IRE1α或激活的X-box结合蛋白1(XBP1)(即规范的IRE1α靶标)来挽救。事实上,IRE1αRNase可处理包括miR-466和miR-200家族在内的微小RNA(miR)子集,IRE1α可以通过其在维持糖尿病状态下的BMPC功能中发挥重要作用。 IRE1α通过独立于XBP1的受调控的IRE1α依赖性衰变(RIDD),在前体miR水平上减弱了miR-466和miR-200家族成员的成熟。糖尿病中的IRE1α缺乏症导致miR-466和miR-200家族功能性miR爆发,它们直接靶向并抑制编码血管生成因子血管生成素1(ANGPT1)的mRNA,从而导致ANGPT1表达降低并破坏了血管生成。重要的是,使用表达IRE1α的BMPC或直接IRE1α基因转移的细胞疗法通过促进血管生成,显着加速了糖尿病小鼠皮肤伤口的愈合。总之,我们的研究揭示了在糖尿病伤口治疗中挽救血管生成和组织修复的新机制基础。

著录项

  • 来源
    《Diabetes》 |2017年第1期|177-192|共16页
  • 作者单位

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI,Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI;

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI;

    Karmanos Cancer Institute, Wayne State University, Detroit, MI;

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI,Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI;

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI,Karmanos Cancer Institute, Wayne State University, Detroit, MI,Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI;

  • 收录信息 美国《科学引文索引》(SCI);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-18 03:46:06

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