SOD2
线粒体
内科学
超氧化物
氧化应激
活性氧
内皮
内分泌学
线粒体ROS
内皮功能障碍
超氧化物歧化酶
生物
化学
生物化学
作者
Atinuke Dosunmu-Ogunbi,Shuai Yuan,Mike Reynolds,Luca Giordano,Subramaniam Sanker,Mara Grove-Sullivan,Donna B. Stolz,Brett A. Kaufman,Katherine C Wood,Yingze Zhang,Sruti Shiva,S. Mehdi Nouraie,Adam C Straub
出处
期刊:Blood
[American Society of Hematology]
日期:2021-12-27
标识
DOI:10.1182/blood.2021013350
摘要
Superoxide dismutase 2 (SOD2) catalyzes the dismutation of superoxide to hydrogen peroxide in mitochondria limiting mitochondrial damage. The SOD2 amino acid valine-to-alanine substitution at position 16 (V16A) in the mitochondrial leader sequence is a common genetic variant among patients with sickle cell disease (SCD). However, little is known about the cardiovascular consequences of SOD2V16A in SCD patients or its impact on endothelial cell function. Here, we show SOD2V16A associates with increased tricuspid regurgitant velocity (TRV), systolic blood pressure, right ventricle area at systole and declined 6-minute walk distance in 410 SCD patients. Plasma lactate dehydrogenase, a marker of oxidative stress and hemolysis, significantly associated with higher TRV. To define the impact of SOD2V16A in the endothelium, we introduced the SOD2V16A variant into endothelial cells. SOD2V16A increases hydrogen peroxide and mitochondrial reactive oxygen species (ROS) production compared to controls. Unexpectedly, the increased ROS was not due to SOD2V16A mislocalization but was associated with mitochondrial Complex IV and a concomitant decrease in basal respiration and Complex IV activity. In sum, SOD2V16A is a novel clinical biomarker of cardiovascular dysfunction in SCD patients through its ability to decrease mitochondrial Complex IV activity and amplify ROS production in the endothelium.
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