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      Endothelial microparticles are increased in congenital heart diseases and contribute to endothelial dysfunction

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          Abstract

          Background

          We previously demonstrated that endothelial microparticles (EMPs) are increased in mitral valve diseases and impair valvular endothelial cell function. Perioperative systemic inflammation is an important risk factor and complication of cardiac surgery. In this study, we investigate whether EMPs increase in congenital heart diseases to promote inflammation and endothelial dysfunction.

          Methods

          The level of plasma EMPs in 20 patients with atrial septal defect (ASD), 23 patients with ventricular septal defect (VSD), and 30 healthy subjects were analyzed by flow cytometry. EMPs generated from human umbilical vascular endothelial cells (HUVECs) were injected into C57BL6 mice, or cultured with HUVECs without or with siRNAs targeting P38 MAPK. The expression and/or phosphorylation of endothelial nitric oxide synthase (eNOS), P38 MAPK, and caveolin-1 in mouse heart and/or in cultured HUVECs were determined. We evaluated generation of nitric oxide (NO) in mouse hearts, and levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cultured HUVECs and in mice.

          Results

          EMPs were significantly elevated in patients with ASD and VSD, especially in those with pulmonary hypertension when compared with controls. EMPs increased caveolin-1 expression and P38 MAPK phosphorylation and decreased eNOS phosphorylation and NO production in mouse hearts. EMPs stimulated P38 MAPK expression, TNF-α and IL-6 production, which were all inhibited by siRNAs targeting P38 MAPK in cultured HUVECs.

          Conclusions

          EMPs were increased in adult patients with congenital heart diseases and may contribute to increased inflammation leading to endothelial dysfunction via P38 MAPK-dependent pathways. This novel data provides a potential therapeutic target to address important complications of surgery of congenial heart disease.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12967-016-1087-2) contains supplementary material, which is available to authorized users.

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          Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension.

          K. Sung, Marina Fridlib, Laszlo Farkas … (2013)
          Pulmonary hypertension (PH) is a serious condition that affects mainly young and middle-aged women, and its etiology is poorly understood. A prominent pathological feature of PH is accumulation of macrophages near the arterioles of the lung. In both clinical tissue and the SU5416 (SU)/athymic rat model of severe PH, we found that the accumulated macrophages expressed high levels of leukotriene A4 hydrolase (LTA4H), the biosynthetic enzyme for leukotriene B4 (LTB4). Moreover, macrophage-derived LTB4 directly induced apoptosis in pulmonary artery endothelial cells (PAECs). Further, LTB4 induced proliferation and hypertrophy of human pulmonary artery smooth muscle cells. We found that LTB4 acted through its receptor, BLT1, to induce PAEC apoptosis by inhibiting the protective endothelial sphingosine kinase 1 (Sphk1)-endothelial nitric oxide synthase (eNOS) pathway. Blocking LTA4H decreased in vivo LTB4 levels, prevented PAEC apoptosis, restored Sphk1-eNOS signaling, and reversed fulminant PH in the SU/athymic rat model of PH. Antagonizing BLT1 similarly reversed established PH. Inhibition of LTB4 biosynthesis or signal transduction in SU-treated athymic rats with established disease also improved cardiac function and reopened obstructed arterioles; this approach was also effective in the monocrotaline model of severe PH. Human plexiform lesions, one hallmark of PH, showed increased numbers of macrophages, which expressed LTA4H, and patients with connective tissue disease-associated pulmonary arterial hypertension exhibited significantly higher LTB4 concentrations in the systemic circulation than did healthy subjects. These results uncover a possible role for macrophage-derived LTB4 in PH pathogenesis and identify a pathway that may be amenable to therapeutic targeting.
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            Endothelium-derived microparticles induce endothelial dysfunction and acute lung injury.

            Yang Shi, R L Sabina, Sushma Kaul … (2006)
            Acute lung injury (ALI) carries a high mortality in critically ill patients. Recent reports correlate elevated concentrations of endothelium-derived microparticles (EMPs) with diseases of endothelial dysfunction. Many of these diseases have ALI sequelae. We hypothesize that EMPs contribute to endothelial cell (EC) dysfunction and development of ALI. To test this hypothesis, we treated isolated vessels with EMPs and examined changes in vasodilation. Endothelial cell cultures were incubated with EMPs and examined for changes in stimulated nitric oxide (*NO) production and nitric oxide synthase (eNOS) activation. Finally, EMPs were injected into rats and mice and lungs examined for ALI. In both mouse and human ex vivo vessel preparations, we found a marked attenuation of endothelium-mediated vasodilation after EMP treatment (4 x 10(6)/mL). This dysfunction was not corrected by pretreatment of EMPs with free radical scavengers. Coincubation of EMPs with EC cultures yielded a three-fold reduction in A23187-stimulated *NO release. Western analysis of these cells showed a corresponding decrease in eNOS phosphorylation at Ser1179 and a decrease in hsp90 association. Measurements of lung permeability, myeloperoxidase activity, and histology of EMPs-treated Brown Norway rats demonstrated pulmonary edema, neutrophil recruitment, and compromise of the endothelial-alveolar barrier as a second hit phenomenon. In C57BL/6 mice, exogenous EMPs caused a significant rise in pulmonary capillary permeability both as a primary and secondary injury. These findings demonstrate EMPs are capable of inducing significant lung injury at pathophysiologically relevant concentrations. Endothelium-derived microparticles inhibit endothelium-mediated vasodilation and *NO generation from eNOS. Once elucidated, EMP mechanisms of inducing ALI and endothelial dysfunction may present new therapeutic targets.
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              Circulating endothelial microparticle levels predict hemodynamic severity of pulmonary hypertension.

              Yerem Yeghiazarians, Christian Heiss, Nicolas Amabile … (2008)
              Circulating microparticles (MPs) are submicron membrane fragments shed from damaged or activated vascular cells. Endothelial MPs are a biological marker of dysfunctional endothelium. Vascular remodeling and endothelial dysfunction are involved in pulmonary hypertension (PH). We tested the hypothesis that circulating MPs are increased in patients with PH and that identifiable subgroups of MPs predict the hemodynamic severity of this condition progression. Patients (n = 24; age, 54 +/- 4 yr) undergoing right heart catheterization for precapillary PH without any endothelium-active vasodilator therapy participated in the study. Age- and sex-matched healthy control subjects (n = 20) were included. Endothelial (PECAM(+) [CD31(+)]/ CD41(-), VE-cadherin(+) [CD144(+)], and E-selectin(+) [CD62e(+)]), platelet (CD41(+)), leukocyte-derived (CD45(+)), and annexin V(+) MPs were measured by flow cytometry in platelet-free plasma from venous blood. Levels of circulating endothelial PECAM(+), VE-cadherin(+), E-selectin(+), and leukocyte-derived MPs, but not platelet and annexin V(+) MPs, were increased in subjects with PH compared with control subjects (P < 0.01 each). PECAM(+) and VE-cadherin(+) MP levels significantly correlated with mean pulmonary artery pressure (r = 0.92 and r = 0.87, respectively), pulmonary vascular resistance (r = 0.78 and r = 0.73), and mean right atrial pressure (r = 0.43, and r = 0.46) and correlated inversely with cardiac index (r = -0.59 and r = -0.52). These relationships were not observed for other MP subgroups, and persisted in multivariate analysis after adjustment for confounding factors. In subjects with precapillary PH, levels of circulating endothelial and leukocyte MPs were increased compared with control subjects. In addition, levels of PECAM(+) and VE-cadherin(+), but not E-selectin(+), endothelial MPs predicted hemodynamic severity of the disease.
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                Author and article information

                Contributors
                Ze-Bang Lin: zebang_lin@hotmail.com
                Hong-Bo Ci: cihongbo111@126.com
                Yan Li: li_yan_lee@126.com
                Tian-Pu Cheng: tempo_pupu@126.com
                Dong-Hong Liu: pyldhjj@hotmail.com
                Yan-Sheng Wang: wangyansheng1999@126.com
                Jun Xu: xufeili@vip.163.com
                Hao-Xiang Yuan: yhxyhx1992@126.com
                Hua-Ming Li: 465575626@qq.com
                Jing Chen: chenjingzale@163.com
                Li Zhou: oskarchow@126.com
                Zhi-Ping Wang: Wangzhip12345@yahoo.com.cn
                Xi Zhang: zhangxisysu@163.com
                Zhi-Jun Ou: zhijunou@163.com
                Jing-Song Ou: 86-20-87755766-8238 , oujs@mail.sysu.edu.cn , oujs2000@yahoo.com
                Journal
                Journal ID (nlm-ta): J Transl Med
                Journal ID (iso-abbrev): J Transl Med
                Title: Journal of Translational Medicine
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1479-5876
                Publication date (Electronic): 4 January 2017
                Publication date PMC-release: 4 January 2017
                Publication date Collection: 2017
                Volume: 15
                Electronic Location Identifier: 4
                Affiliations
                [1 ]Division of Cardiac Surgery, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhong Shan Er Road, Guangzhou, 510080 People’s Republic of China
                [2 ]Department of Ultrasound, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080 People’s Republic of China
                [3 ]Division of Hypertension and Vascular Diseases, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080 People’s Republic of China
                [4 ]The Key Laboratory of Assisted Circulation, Ministry of Health, Guangzhou, 510080 People’s Republic of China
                [5 ]National and Guangdong Province Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Diseases, Guangzhou, 510080 People’s Republic of China
                [6 ]Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, 510080 People’s Republic of China
                [7 ]State Key Laboratory of Respiratory Disease, Guangzhou, 510080 People’s Republic of China
                [8 ]Guangzhou Institute of Respiratory Disease, Guangzhou, 510080 People’s Republic of China
                [9 ]The First Affiliated Hospital of Guangzhou Medical University Guangzhou, Guangzhou, 510120 People’s Republic of China
                Article
                Publisher ID: 1087
                DOI: 10.1186/s12967-016-1087-2
                PMC ID: 5210308
                PubMed ID: 28049487
                SO-VID: e3674276-10d0-43d1-832c-3a006173f29e
                Copyright © © The Author(s) 2016
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 13 July 2016
                Date accepted : 18 November 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: (81170271, 81325001
                Award Recipient :
                Funded by: the Chang Jiang Scholars Program from Ministry of Education of China
                Funded by: the Guangdong Pearl River Scholars Program
                Funded by: International Cooperation Project from the Ministry of Science and Technology of China
                Award ID: 2015DFA31070
                Award Recipient :
                Funded by: Guangdong Natural Science Fund Committee, China
                Award ID: 2015A030312009
                Award Recipient :
                Funded by: Sun Yat-Sen University Clinical Research 5010 Program
                Funded by: Program of National Key Clinical Specialties
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81370370,81670392
                Award Recipient :
                Funded by: 973 project from the Ministry of Science and Technology of China
                Award ID: 2009CB522104
                Award Recipient :
                Funded by: National Natural Science Foundation of China (CN)
                Award ID: 81500215
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81600382
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Medicine
                Keywords: endothelial microparticles,congenital heart disease,inflammation,endothelial nitric oxide synthase,p38 mapk pathway
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: endothelial microparticles, congenital heart disease, inflammation, endothelial nitric oxide synthase, p38 mapk pathway

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