Omentin reduces venous neointimal hyperplasia in arteriovenous fistula through hypoxia-inducible factor-1 alpha inhibition

IF 2.9 4区 医学 Q2 PERIPHERAL VASCULAR DISEASE
Li Zhui, Chen Yuling, Wang Hansheng, Li Xiangjie
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引用次数: 0

Abstract

Arteriovenous fistula (AVF) failure often involves venous neointimal hyperplasia (VNH) driven by elevated hypoxia-inducible factor-1 alpha (HIF-1α) in the venous wall. Omentin, known for its anti-inflammatory and anti-hyperplasia properties, has an uncertain role in early AVF failure. This study investigates omentin's impact on VNH using a chronic renal failure (CRF) rabbit model. The CRF rabbit model of AVF received omentin-expressing adenoviral vector or control β-gal vector to assess omentin's effects on VNH. Human vascular smooth muscle cells (HVSMCs), stimulated with tumor necrosis factor-α (TNF-α), were exposed to recombinant human omentin (Rh-OMT) to study its influence on cell proliferation and migration. The AMP-activated protein kinase (AMPK) inhibitor compound C and the mammalian target of rapamycin (mTOR) activator MHY1485 were employed to explore omentin's mechanisms in VNH reduction through HIF-1α inhibition. Omentin treatment reduced VNH in CRF rabbits, concomitant with HIF-1α down-regulation and the suppression of downstream factors, including vascular endothelial growth factor and matrix metalloproteinases. Rh-OMT inhibited TNF-α-induced HVSMC proliferation and migration by modulating both cell cycle and cell adhesion proteins. Additionally, omentin reduced HIF-1α expression through the AMPK/mTOR pathway activation. Notably, the blockade of AMPK/mTOR signaling reversed omentin-mediated inhibition of VNH, cell proliferation, and migration, both in vivo and in vitro. In conclusion, omentin mitigates VNH post-AVF creation by restraining HIF-1α via AMPK/mTOR signaling. Strategies boosting circulating omentin levels may offer promise in averting AVF failure.

网膜素通过抑制低氧诱导因子-1α减少动静脉瘘的静脉新生血管增生。
动静脉瘘(AVF)衰竭通常涉及静脉壁缺氧诱导因子-1α(HIF-1α)升高导致的静脉新内膜增生(VNH)。网膜素以其抗炎和抗增生的特性而闻名,但它在 AVF 早期衰竭中的作用尚不确定。本研究利用慢性肾功能衰竭(CRF)兔模型研究了奥门汀对 VNH 的影响。CRF兔动静脉瘘模型接受了表达网织红霉素的腺病毒载体或对照β-gal载体,以评估网织红霉素对VNH的影响。用肿瘤坏死因子-α(TNF-α)刺激人血管平滑肌细胞(HVSMC),使其暴露于重组人网膜素(Rh-OMT),以研究其对细胞增殖和迁移的影响。研究人员使用AMP激活蛋白激酶(AMPK)抑制剂化合物C和哺乳动物雷帕霉素靶标(mTOR)激活剂MHY1485来探索网织蛋白通过抑制HIF-1α降低VNH的机制。在HIF-1α下调、包括血管内皮生长因子和基质金属蛋白酶在内的下游因子受到抑制的同时,网膜素治疗降低了CRF兔的VNH。Rh-OMT通过调节细胞周期和细胞粘附蛋白,抑制了TNF-α诱导的HVSMC增殖和迁移。此外,奥门冬酰胺还能通过激活 AMPK/mTOR 通路减少 HIF-1α 的表达。值得注意的是,无论是在体内还是体外,阻断 AMPK/mTOR 信号转导都能逆转奥门汀介导的对 VNH、细胞增殖和迁移的抑制作用。总之,网脱素能通过AMPK/mTOR信号转导抑制HIF-1α,从而减轻AVF形成后的VNH。提高循环中网膜素水平的策略有望避免动静脉瘘失败。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Microvascular research
Microvascular research 医学-外周血管病
CiteScore
6.00
自引率
3.20%
发文量
158
审稿时长
43 days
期刊介绍: Microvascular Research is dedicated to the dissemination of fundamental information related to the microvascular field. Full-length articles presenting the results of original research and brief communications are featured. Research Areas include: • Angiogenesis • Biochemistry • Bioengineering • Biomathematics • Biophysics • Cancer • Circulatory homeostasis • Comparative physiology • Drug delivery • Neuropharmacology • Microvascular pathology • Rheology • Tissue Engineering.
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