Necessary Role of Ceramides in the Human Microvascular Endothelium During Health and Disease

Author:

SenthilKumar Gopika123ORCID,Katunaric Boran3,Zirgibel Zachary23,Lindemer Brian23ORCID,Jaramillo-Torres Maria J.23ORCID,Bordas-Murphy Henry23,Schulz Mary E.23,Pearson Paul J.4,Freed Julie K.123ORCID

Affiliation:

1. Department of Physiology (G.S., J.K.F.), Medical College of Wisconsin, Milwaukee, WI.

2. Cardiovascular Center (G.S., Z.Z., B.L., M.J.J.-T., H.B.-M., M.E.S., J.K.F.), Medical College of Wisconsin, Milwaukee, WI.

3. Department of Anesthesiology (G.S., B.K., Z.Z., B.L., M.J.J.-T., H.B.-M., M.E.S., J.K.F.), Medical College of Wisconsin, Milwaukee, WI.

4. Department of Surgery, Division of Cardiothoracic Surgery (P.J.P.), Medical College of Wisconsin, Milwaukee, WI.

Abstract

Background: Elevated plasma ceramides and microvascular dysfunction both independently predict adverse cardiac events. Despite the known detrimental effects of ceramide on the microvasculature, evidence suggests that activation of the shear-sensitive, ceramide-forming enzyme NSmase (neutral sphingomyelinase) elicits formation of vasoprotective nitric oxide (NO). Here, we explore a novel hypothesis that acute ceramide formation through NSmase is necessary for maintaining NO signaling within the human microvascular endothelium. We further define the mechanism through which ceramide exerts beneficial effects and discern key mechanistic differences between arterioles from otherwise healthy adults (non–coronary artery disease [CAD]) and patients diagnosed with CAD. Methods: Human arterioles were dissected from discarded surgical adipose tissue (n=166), and vascular reactivity to flow and C2-ceramide was assessed. Shear-induced NO and mitochondrial hydrogen peroxide (H 2 O 2 ) production were measured in arterioles using fluorescence microscopy. H 2 O 2 fluorescence was assessed in isolated human umbilical vein endothelial cells. Results: Inhibition of NSmase in arterioles from otherwise healthy adults induced a switch from NO to NOX-2 (NADPH-oxidase 2)–dependent H 2 O 2 -mediated flow-induced dilation. Endothelial dysfunction was prevented by treatment with sphingosine-1-phosphate (S1P) and partially prevented by C2-ceramide and an agonist of S1P-receptor 1 (S1PR1); the inhibition of the S1P/S1PR1 signaling axis induced endothelial dysfunction via NOX-2. Ceramide increased NO production in arterioles from non-CAD adults, an effect that was diminished with inhibition of S1P/S1PR1/S1P-receptor 3 signaling. In arterioles from patients with CAD, inhibition of NSmase impaired the overall ability to induce mitochondrial H 2 O 2 production and subsequently dilate to flow, an effect not restored with exogenous S1P. Acute ceramide administration to arterioles from patients with CAD promoted H 2 O 2 as opposed to NO production, an effect dependent on S1P-receptor 3 signaling. Conclusion: These data suggest that despite differential downstream signaling between health and disease, NSmase-mediated ceramide formation is necessary for proper functioning of the human microvascular endothelium. Therapeutic strategies that aim to significantly lower ceramide formation may prove detrimental to the microvasculature.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

Cited by 6 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