title: Inhibiting the Th17/IL-17A-related inflammatory responses with digoxin confers protection against experimental abdominal aortic aneurysm.
abstract: OBJECTIVE
  T helper 17 cells and interleukin-17A have been implicated in the progression of abdominal aortic aneurysm (AAA). Retinoic acid-related orphan receptor gamma thymus, the master transcription factor of T helper 17 cell differentiation, is selectively antagonized by digoxin. However, the effect of antagonizing retinoic acid-related orphan receptor gamma thymus on AAA has not been investigated.
  
  
  RESULTS
  We used human aortic sample analysis and 2 different experimental AAA models: (a) Angiotensin II (Ang II)-induced ApoE(-/-) male mice (Ang II/APOE model) and (b) porcine pancreatic elastase perfusion C57BL/6 mice (porcine pancreatic elastase/C57 model). In the Ang II/APOE model, all mice (n=80) were divided into 4 groups: sham group (saline+0.5% dimethyl sulfoxide treatment), control group (Ang II+0.5% dimethyl sulfoxide treatment), low-dose group (Ang II+low-dose digoxin, 20 μg/d per mouse), and high-dose group (Ang II+high-dose digoxin, 40 μg/d per mouse). All treatments began on day 0 after surgery. Efficacy was determined via aortic diameter and systolic blood pressure measurements, histopathology and protein expression, and flow cytometry analysis when euthenized. Human aortic tissue analysis showed that both interleukin-17A and retinoic acid-related orphan receptor gamma thymus increased in AAA tissues. The low-dose and high-dose groups had AAA incidences of 60% and 35%, respectively, compared with 70% in the control group. The T helper 17- and interleukin-17A-related inflammatory responses were dose-dependently attenuated by digoxin treatment. Digoxin was also highly effective in the porcine pancreatic elastase/C57 model.
  
  
  CONCLUSIONS
  Digoxin attenuates experimental AAA progression in a model-independent manner. Antagonizing retinoic acid-related orphan receptor gamma thymus activity by digoxin may become a novel strategy for nonsurgical AAA treatment.
authors.affiliation: From the Department of Cardiovascular Surgery, Union Hospital (Z.W., K.Z., Y.L., P.Y., J.W., Y.W., F.L., J.L.) and Department of Biochemistry and Molecular Biology (Y.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Central Hospital of Wuhan, Wuhan, China (P.Y.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research (Y.Y.) and Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College (Y.Z.), Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Zhanjie
authors.initials: Z
authors.lastname: Wei
authors.affiliation: From the Department of Cardiovascular Surgery, Union Hospital (Z.W., K.Z., Y.L., P.Y., J.W., Y.W., F.L., J.L.) and Department of Biochemistry and Molecular Biology (Y.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Central Hospital of Wuhan, Wuhan, China (P.Y.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research (Y.Y.) and Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College (Y.Z.), Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Department of Cardiovascular Surgery, Union Hospital (Z.W., K.Z., Y.L., P.Y., J.W., Y.W., F.L., J.L.) and Department of Biochemistry and Molecular Biology (Y.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Central Hospital of Wuhan, Wuhan, China (P.Y.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research (Y.Y.) and Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College (Y.Z.), Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Kailun
authors.initials: K
authors.lastname: Zhang
authors.affiliation: From the Department of Cardiovascular Surgery, Union Hospital (Z.W., K.Z., Y.L., P.Y., J.W., Y.W., F.L., J.L.) and Department of Biochemistry and Molecular Biology (Y.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Central Hospital of Wuhan, Wuhan, China (P.Y.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research (Y.Y.) and Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College (Y.Z.), Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yaohang
authors.initials: Y
authors.lastname: Liao
authors.affiliation: From the Department of Cardiovascular Surgery, Union Hospital (Z.W., K.Z., Y.L., P.Y., J.W., Y.W., F.L., J.L.) and Department of Biochemistry and Molecular Biology (Y.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Central Hospital of Wuhan, Wuhan, China (P.Y.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research (Y.Y.) and Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College (Y.Z.), Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ye
authors.affiliation: From the Department of Cardiovascular Surgery, Union Hospital (Z.W., K.Z., Y.L., P.Y., J.W., Y.W., F.L., J.L.) and Department of Biochemistry and Molecular Biology (Y.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Central Hospital of Wuhan, Wuhan, China (P.Y.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research (Y.Y.) and Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College (Y.Z.), Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: From the Department of Cardiovascular Surgery, Union Hospital (Z.W., K.Z., Y.L., P.Y., J.W., Y.W., F.L., J.L.) and Department of Biochemistry and Molecular Biology (Y.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Central Hospital of Wuhan, Wuhan, China (P.Y.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research (Y.Y.) and Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College (Y.Z.), Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Department of Cardiovascular Surgery, Union Hospital (Z.W., K.Z., Y.L., P.Y., J.W., Y.W., F.L., J.L.) and Department of Biochemistry and Molecular Biology (Y.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Central Hospital of Wuhan, Wuhan, China (P.Y.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research (Y.Y.) and Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College (Y.Z.), Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Li
authors.affiliation: From the Department of Cardiovascular Surgery, Union Hospital (Z.W., K.Z., Y.L., P.Y., J.W., Y.W., F.L., J.L.) and Department of Biochemistry and Molecular Biology (Y.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Central Hospital of Wuhan, Wuhan, China (P.Y.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research (Y.Y.) and Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College (Y.Z.), Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Yao
authors.affiliation: From the Department of Cardiovascular Surgery, Union Hospital (Z.W., K.Z., Y.L., P.Y., J.W., Y.W., F.L., J.L.) and Department of Biochemistry and Molecular Biology (Y.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Central Hospital of Wuhan, Wuhan, China (P.Y.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research (Y.Y.) and Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College (Y.Z.), Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yanzhao
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: From the Department of Cardiovascular Surgery, Union Hospital (Z.W., K.Z., Y.L., P.Y., J.W., Y.W., F.L., J.L.) and Department of Biochemistry and Molecular Biology (Y.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiology, Central Hospital of Wuhan, Wuhan, China (P.Y.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center for Human Genome Research (Y.Y.) and Laboratory of Cardiovascular Immunology, Key Laboratory of Molecular Targeted Therapies of the Ministry of Education, Institute of Cardiology, Union Hospital, Tongji Medical College (Y.Z.), Huazhong University of Science and Technology, Wuhan, China. jinping@hust.edu.cn.
authors.forename: Jinping
authors.initials: J
authors.lastname: Liu
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D004077:Digoxin / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D010196:Pancreatic Elastase / Q000009:adverse effects; D015996:Survival Rate; D013552:Swine; D058504:Th17 Cells / Q000187:drug effects* / Q000473:pathology*
chemical_list: D001057:Apolipoproteins E; D002316:Cardiotonic Agents; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D000804:Angiotensin II; D004077:Digoxin; D010196:Pancreatic Elastase
keywords: IL-17A; abdominal aortic aneurysm; digoxin; inflammation