Abstract 17224: Metabolic Switch and Redox Imbalance Contributes to Pulmonary Hypertension in Glucose-6-Phosphate Dehydrogenase Deficiency

磷酸戊糖途径 医学 氧化应激 肺动脉高压 缺氧(环境) 内科学 发病机制 氧化磷酸化 内分泌学 下调和上调 糖酵解 葡萄糖-6-磷酸脱氢酶 葡萄糖-6-磷酸脱氢酶缺乏症 丙酮酸脱氢酶复合物 脱氢酶 新陈代谢 生物化学 生物 化学 氧气 基因 有机化学
作者
Mathews Valuparampil Varghes,Joel James,Olga Rafikova,Ruslan Rafikov
出处
期刊:Circulation [Lippincott Williams & Wilkins]
卷期号:142 (Suppl_3)
标识
DOI:10.1161/circ.142.suppl_3.17224
摘要

Introduction: Pulmonary hypertension (PH) is a fatal disorder with inadequate therapeutic choices and diminished survival rate with later prognosis. We previously reported that several patients with idiopathic pulmonary arterial hypertension had different types of glucose-6 phosphate dehydrogenase (G6PD) deficiency. G6PD is the key regulator enzyme in the pentose phosphate pathway (PPP) and the only source of NADPH in erythrocytes. However, the pathogenic mechanism of how G6PD deficiency contributes to PH development remains elusive. Hypothesis: We hypothesize that G6PD deficiency-induced PH is mediated through a multifactorial mechanism by increased red blood cell fragility, oxidative stress, and a metabolic switch. Methods: To delineate the contribution of G6PD in PH pathogenesis, we utilized a G6PD knockdown mouse line (11-13 week old) with decreased expression of G6PD (10% from wild-type level). Results: Hemodynamic and histological studies confirmed that G6PD deficient mice developed PH phenotype by an increase in right ventricular systolic pressure (30.08±0.91mmHg; p≤0.001), Fulton index (0.358±0.03; p≤0.01) and pulmonary vascular remodeling. G6PD deficiency resulted in increased free hemoglobin and activation of the p38/MAPK pathway, which we recently reported, induces the development of PH in the sugen/hypoxia model via endothelial barrier dysfunction. Metabolomics analysis of G6PD-deficient mice indicates the switch to alternative metabolic fluxes that feed into PPP, resulting in the upregulation of oxidative stress, fatty acid pathway, and reduction in pyruvate production. Thus, G6PD deficiency did not reduce PPP flux that is important for proliferation but activated collateral pathways at the cost of increased oxidative stress. Indeed, we found upregulation of Myo-inositol oxidase (p≤0.05), reduction in GSH/GSSG ratio (p≤0.01), and increased nitration (p≤0.05) in the lungs of G6PD deficient mice. Increased oxidative stress also results in the activation of PI3K, ERK1/2 and AMPK that contributes to the proliferation of pulmonary vasculature. Conclusions: Based on these results we infer that G6PD deficiency has a multi-modal effect, including hemolysis, metabolic reprogramming, and oxidative stress leading to PH.

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
yx_cheng应助马旭辉采纳,获得10
2秒前
霜之哀伤发布了新的文献求助20
2秒前
无限的妙菡完成签到 ,获得积分10
4秒前
南方姑娘发布了新的文献求助10
5秒前
5秒前
美丽的依霜完成签到 ,获得积分10
6秒前
6秒前
科研通AI5应助唠叨的严青采纳,获得10
7秒前
威武皮带完成签到,获得积分10
9秒前
11发布了新的文献求助10
11秒前
Rondab应助马旭辉采纳,获得10
12秒前
辰昜完成签到 ,获得积分10
15秒前
18秒前
桐桐应助11采纳,获得10
19秒前
阿纯完成签到,获得积分10
20秒前
南方姑娘完成签到,获得积分10
20秒前
李爱国应助何征结采纳,获得10
21秒前
不安静白完成签到 ,获得积分20
24秒前
wanci应助科研通管家采纳,获得10
24秒前
李健应助科研通管家采纳,获得10
24秒前
天天快乐应助科研通管家采纳,获得10
24秒前
香蕉觅云应助科研通管家采纳,获得10
24秒前
深情安青应助科研通管家采纳,获得10
24秒前
Lc应助科研通管家采纳,获得10
24秒前
Lc应助科研通管家采纳,获得10
24秒前
完美世界应助科研通管家采纳,获得10
25秒前
Owen应助nananan采纳,获得10
25秒前
脑洞疼应助科研通管家采纳,获得10
25秒前
25秒前
25秒前
25秒前
26秒前
26秒前
万能图书馆应助霜之哀伤采纳,获得30
27秒前
Rondab应助Francois采纳,获得10
28秒前
马旭辉完成签到,获得积分20
28秒前
30秒前
30秒前
lzm发布了新的文献求助10
33秒前
活泼水桃发布了新的文献求助20
33秒前
高分求助中
The Mother of All Tableaux: Order, Equivalence, and Geometry in the Large-scale Structure of Optimality Theory 3000
A new approach to the extrapolation of accelerated life test data 1000
Indomethacinのヒトにおける経皮吸収 400
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 370
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
Aktuelle Entwicklungen in der linguistischen Forschung 300
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3993004
求助须知:如何正确求助?哪些是违规求助? 3533831
关于积分的说明 11263946
捐赠科研通 3273597
什么是DOI,文献DOI怎么找? 1806129
邀请新用户注册赠送积分活动 882968
科研通“疑难数据库(出版商)”最低求助积分说明 809629