NADPH Oxidase 4: Crucial for Endothelial Function under Hypoxia-Complementing Prostacyclin.

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Heike Brendel, Jennifer Mittag, Anja Hofmann, Helene Hempel, Sindy Giebe, Patrick Diaba-Nuhoho, Steffen Wolk, Christian Reeps, Henning Morawietz, Coy Brunssen
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引用次数: 0

Abstract

Aim: The primary endothelial NADPH oxidase isoform 4 (NOX4) is notably induced during hypoxia, with emerging evidence suggesting its vasoprotective role through H2O2 production. Therefore, we aimed to elucidate NOX4's significance in endothelial function under hypoxia. Methods: Human vessels, in addition to murine vessels from Nox4-/- mice, were explored. On a functional level, Mulvany myograph experiments were performed. To obtain mechanistical insights, human endothelial cells were cultured under hypoxia with inhibitors of hypoxia-inducible factors. Additionally, endothelial cells were cultured under combined hypoxia and laminar shear stress conditions. Results: In human occluded vessels, NOX4 expression strongly correlated with prostaglandin I2 synthase (PTGIS). Hypoxia significantly elevated NOX4 and PTGIS expression and activity in human endothelial cells. Inhibition of prolyl hydroxylase domain (PHD) enzymes, which stabilize hypoxia-inducible factors (HIFs), increased NOX4 and PTGIS expression even under normoxic conditions. NOX4 mRNA expression was reduced by HIF1a inhibition, while PTGIS mRNA expression was only affected by the inhibition of HIF2a under hypoxia. Endothelial function assessments revealed hypoxia-induced endothelial dysfunction in mesenteric arteries from wild-type mice. Mesenteric arteries from Nox4-/- mice exhibited an altered endothelial function under hypoxia, most prominent in the presence of cyclooxygenase inhibitor diclofenac to exclude the impact of prostacyclin. Restored protective laminar shear stress, as it might occur after thrombolysis, angioplasty, or stenting, attenuated the hypoxic response in endothelial cells, reducing HIF1a expression and its target NOX4 while enhancing eNOS expression. Conclusions: Hypoxia strongly induces NOX4 and PTGIS, with a close correlation between both factors in occluded, hypoxic human vessels. This relationship ensured endothelium-dependent vasodilation under hypoxic conditions. Protective laminar blood flow restores eNOS expression and mitigates the hypoxic response on NOX4 and PTGIS.

NADPH 氧化酶 4:缺氧条件下内皮功能的关键--补充前列环素。
目的:缺氧时会明显诱导初级内皮 NADPH 氧化酶同工酶 4(NOX4),新的证据表明它通过产生 H2O2 起到保护血管的作用。因此,我们旨在阐明 NOX4 在缺氧条件下对内皮功能的重要作用。方法:除了研究 Nox4-/- 小鼠的小鼠血管外,我们还研究了人类血管。在功能层面,进行了 Mulvany 肌电图实验。为了深入了解机理,使用低氧诱导因子抑制剂在低氧条件下培养人类内皮细胞。此外,还在缺氧和层流剪切应力条件下培养内皮细胞。结果在人体闭塞血管中,NOX4的表达与前列腺素I2合成酶(PTGIS)密切相关。缺氧会明显提高人内皮细胞中 NOX4 和 PTGIS 的表达和活性。脯氨酰羟化酶结构域(PHD)酶能稳定缺氧诱导因子(HIF),即使在正常缺氧条件下,抑制该酶也会增加 NOX4 和 PTGIS 的表达。抑制 HIF1a 会降低 NOX4 mRNA 的表达,而 PTGIS mRNA 的表达只受缺氧条件下抑制 HIF2a 的影响。内皮功能评估显示,缺氧诱导野生型小鼠肠系膜动脉内皮功能障碍。Nox4-/-小鼠的肠系膜动脉在缺氧条件下表现出内皮功能的改变,在环氧化酶抑制剂双氯芬酸的作用下最为明显,从而排除了前列环素的影响。在溶栓、血管成形术或支架植入术后恢复的保护性层流剪切应力减轻了内皮细胞的缺氧反应,降低了 HIF1a 的表达及其靶标 NOX4 的表达,同时增强了 eNOS 的表达。结论缺氧会强烈诱导 NOX4 和 PTGIS,在闭塞、缺氧的人体血管中,这两个因素之间存在密切的相关性。这种关系确保了缺氧条件下内皮依赖性血管扩张。保护性层流可恢复 eNOS 的表达,减轻缺氧对 NOX4 和 PTGIS 的影响。
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
Antioxidants
Antioxidants Biochemistry, Genetics and Molecular Biology-Physiology
CiteScore
10.60
自引率
11.40%
发文量
2123
审稿时长
16.3 days
期刊介绍: Antioxidants (ISSN 2076-3921), provides an advanced forum for studies related to the science and technology of antioxidants. It publishes research papers, reviews and communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. Electronic files and software regarding the full details of the calculation or experimental procedure, if unable to be published in a normal way, can be deposited as supplementary electronic material.
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