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
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]
日期:2020-11-17
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.
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