Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability

Author:

Hsu Lewis L.12,Champion Hunter C.3,Campbell-Lee Sally A.4,Bivalacqua Trinity J.3,Manci Elizabeth A.5,Diwan Bhalchandra A.6,Schimel Daniel M.7,Cochard Audrey E.2,Wang Xunde8,Schechter Alan N.9,Noguchi Constance T.9,Gladwin Mark T.289

Affiliation:

1. Marian Anderson Sickle Cell Center at St Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA;

2. Critical Care Medicine Department, Clinical Center, National Institutes of Health (NIH), Bethesda, MD;

3. Johns Hopkins University, Baltimore, MD;

4. Transfusion Medicine, Department of Pathology, University of Illinois at Chicago;

5. Sickle Cell Pathology Unit, University of South Alabama, Mobile;

6. Basic Research Program, Science Applications International Corporation (SAIC)–Frederick, National Cancer Institute at Frederick (NCI-Frederick), MD;

7. Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD;

8. Vascular Medicine Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD;

9. Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD

Abstract

AbstractPulmonary hypertension is a highly prevalent complication of sickle cell disease and is a strong risk factor for early mortality. However, the pathophysiologic mechanisms leading to pulmonary vasculopathy remain unclear. Transgenic mice provide opportunities for mechanistic studies of vascular pathophysiology in an animal model. By microcardiac catheterization, all mice expressing exclusively human sickle hemoglobin had pulmonary hypertension, profound pulmonary and systemic endothelial dysfunction, and vascular instability characterized by diminished responses to authentic nitric oxide (NO), NO donors, and endothelium-dependent vasodilators and enhanced responses to vasoconstrictors. However, endothelium-independent vasodilation in sickle mice was normal. Mechanisms of vasculopathy in sickle mice involve global dysregulation of the NO axis: impaired constitutive nitric oxide synthase activity (NOS) with loss of endothelial NOS (eNOS) dimerization, increased NO scavenging by plasma hemoglobin and superoxide, increased arginase activity, and depleted intravascular nitrite reserves. Light microscopy and computed tomography revealed no plexogenic arterial remodeling or thrombi/emboli. Transplanting sickle marrow into wild-type mice conferred the same phenotype, and similar pathobiology was observed in a nonsickle mouse model of acute alloimmune hemolysis. Although the time course is shorter than typical pulmonary hypertension in human sickle cell disease, these results demonstrate that hemolytic anemia is sufficient to produce endothelial dysfunction and global dysregulation of NO.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Cited by 219 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3