title: Angiotensin II receptor type 1 autoantibodies promote endothelial microparticles formation through activating p38 MAPK pathway.
abstract: BACKGROUND
  Endothelial microparticles (EMPs) are small vesicular structures that serve as a marker of endothelial function. Angiotensin II receptor type 1 autoantibody (AT1-AA) can cause endothelial dysfunction. However, whether AT1-AA promotes EMPs formation and the mechanism remains obscure.
  
  
  METHODS
  The titres of sera AT1-AA of 126 hypertensive patients and 30 normotensive individuals were evaluated by ELISA. EMPs in the sera and the supernatants of human umbilical vein endothelial cells (HUVECs) were measured by flow cytometry. The phosphorylation levels of mitogen-activated protein kinase (MAPK) pathways in HUVECs treated by AT1-AA were assessed and their correlation with microparticle formation was also analysed. Furthermore, the production of intracellular reactive oxygen species (ROS) and nitric oxide in HUVECs was examined after incubation with 'injured' endothelial microparticle (iEMPs) (EMPs derived from AT1-AA treated HUVECs).
  
  
  RESULTS
  The positive rate of AT1-AA in 126 hypertensive patients was 21.4% (27/126), and higher than that in normotensive individuals [3.3% (1/30), P < 0.01]. Circulating EMP (CD31+/CD42b-) levels were corresponding to the AT1-AA titres in hypertensive group (r(2) = 0.3661, P < 0.01). AT1-AA promoted EMPs generation from HUVECs in a time and dose-dependent manner than the vehicle or nonspecific IgG. Meanwhile, AT1-AA significantly elevated phosphorylation level of P38 and ERK in HUVECs. Lorsartan and P38 inhibitor could suppress the AT1-AA's stimulation effect on EMPs generation. Moreover, the iEMP greatly increased ROS production and reduced nitric oxide synthesis in HUVECs.
  
  
  CONCLUSIONS
  Our findings showed that circulating EMPs levels positively correlate to the serum AT1-AA titres in essential hypertension patients. The AT1-AA could promote EMPs generation in HUVECs through activation of P38 MAPK signalling pathway, and this effect could be effectively inhibited by losartan or p38 inhibitor. Angiotensin receptor blockers (ARBs) may be more suitable for AT1-AA(+) hypertensive patients on account of suppressing the AT1-AA's stimulation effect on EMPs generation.
authors.affiliation: aLaboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology bDepartment of Cardiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China *These authors contributed to the work equally.
authors.forename: Shijun
authors.initials: S
authors.lastname: Yang
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhong
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Qiu
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.forename: Fen
authors.initials: F
authors.lastname: Chen
authors.forename: Khamis
authors.initials: K
authors.lastname: Mustafa
authors.forename: Dan
authors.initials: D
authors.lastname: Ding
authors.forename: Yanzhao
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jibin
authors.initials: J
authors.lastname: Lin
authors.forename: Sen
authors.initials: S
authors.lastname: Yan
authors.forename: Yihuan
authors.initials: Y
authors.lastname: Deng
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Yingling
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Liao
authors.forename: Zihua
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000328:Adult; D001323:Autoantibodies / Q000097:blood / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension / Q000097:blood*; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C544065:AGTR1 protein, human; D001323:Autoantibodies; D007074:Immunoglobulin G; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D009569:Nitric Oxide; D048051:p38 Mitogen-Activated Protein Kinases