晚期糖基化终产物通过构成性内皮RAGE和Nox1/4抑制大鼠离体骨骼肌动脉的扩张。

IF 1.9 4区 医学 Q3 HEMATOLOGY Microcirculation Pub Date : 2023-11-20 DOI:10.1111/micc.12837
Nadim Naser, Chenchel K. Lonj, Matthew Rikard-Bell, Shaun L. Sandow, Timothy V. Murphy
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引用次数: 0

摘要

目的:研究晚期糖基化终产物(AGE)及其受体(RAGE)和NAD(P)H氧化酶(Nox)亚型1、2和4对大鼠肌动脉(CMA)内皮依赖性扩张的作用机制。方法:采用免疫荧光法检测RAGE在大鼠动脉组织中的表达。用发光和荧光法测定ROS积累。使用压力肌图进行功能研究。结果:RAGE在CMA内皮细胞中呈高表达,而在大脑中动脉、肠系膜动脉和主动脉中呈低表达。外源性AGE(体外糖化牛血清白蛋白)刺激CMA中H2O2的积累,RAGE拮抗剂FPS-ZM1和NAD(P)H氧化酶(Nox)抑制剂apocynin可以阻止H2O2的积累,Nox1/4抑制剂setanaxb可以抑制H2O2的积累,但Nox2抑制剂GSK2795039不能抑制H2O2的积累。在功能研究中,AGE抑制乙酰胆碱、硝普钠和BKCa激活剂NS1619刺激的CMA血管舒张,但不抑制腺苷诱导的舒张。FPS-ZM1、罗布麻素和西他那西可阻止AGE对乙酰胆碱和NS-1619的抑制作用。结论:RAGE在大鼠CMA的内皮中组成性表达,并可能被AGE激活,刺激Nox1/4和ROS的形成,从而抑制NO和bkca介导的内皮依赖性扩张。
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Advanced glycated end-products inhibit dilation through constitutive endothelial RAGE and Nox1/4 in rat isolated skeletal muscle arteries

Objective

This study investigated the actions of advanced glycated end-products (AGE), their receptors (RAGE), and NAD(P)H oxidase (Nox) subtypes 1, 2, and 4 on mechanisms of endothelium-dependent dilation of the rat cremaster muscle artery (CMA).

Methods

Immunofluorescence studies were used to examine expression of RAGE in rat arteries. ROS accumulation was measured using luminescence and fluorescence assays. Functional studies were performed using pressure myography.

Results

High levels of RAGE expression were shown in the endothelial cells of the CMA, compared with low endothelial expression in middle cerebral and mesenteric arteries and the aorta. Exogenous AGE (in vitro glycated bovine serum albumin) stimulated H2O2 accumulation in CMA, which was prevented by the RAGE antagonist FPS-ZM1, the NAD(P)H oxidase (Nox) inhibitor apocynin and inhibited by the Nox1/4 inhibitor setanaxib, but not the Nox2 inhibitor GSK2795039. In functional studies, AGE inhibited vasodilation of CMA stimulated by acetylcholine, sodium nitroprusside, and the BKCa activator NS1619, but not adenosine-induced dilation. FPS-ZM1, apocynin, and setanaxib prevented the inhibitory effects of AGE on responses to acetylcholine and NS-1619.

Conclusion

These observations suggest RAGE are constitutively expressed in the endothelium of the rat CMA and may be activated by AGE to stimulate Nox1/4 and ROS formation with resulting inhibition of NO and BKCa-mediated endothelium-dependent dilation.

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来源期刊
Microcirculation
Microcirculation 医学-外周血管病
CiteScore
5.00
自引率
4.20%
发文量
43
审稿时长
6-12 weeks
期刊介绍: The journal features original contributions that are the result of investigations contributing significant new information relating to the vascular and lymphatic microcirculation addressed at the intact animal, organ, cellular, or molecular level. Papers describe applications of the methods of physiology, biophysics, bioengineering, genetics, cell biology, biochemistry, and molecular biology to problems in microcirculation. Microcirculation also publishes state-of-the-art reviews that address frontier areas or new advances in technology in the fields of microcirculatory disease and function. Specific areas of interest include: Angiogenesis, growth and remodeling; Transport and exchange of gasses and solutes; Rheology and biorheology; Endothelial cell biology and metabolism; Interactions between endothelium, smooth muscle, parenchymal cells, leukocytes and platelets; Regulation of vasomotor tone; and Microvascular structures, imaging and morphometry. Papers also describe innovations in experimental techniques and instrumentation for studying all aspects of microcirculatory structure and function.
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