title: Inhibition of BET bromodomain attenuates angiotensin II induced abdominal aortic aneurysm in ApoE-/-mice.
abstract: BACKGROUND
  Excessive degradation of extracellular matrix by matrix metalloproteinases (MMP) is the major pathological feature of abdominal aortic aneurysm (AAA). Suppression of extracellular matrix degradation attenuates AAA initiation and progression in preclinical models. In the present study, we wanted to test the effect of JQ1, a small chemical molecule that selectively targets bromodomain and extra-terminal domain (BET), on AngII induced AAA formation in ApoE-/-mice.
  
  
  RESULTS
  To study the role of BET bromodomain in AAA pathogenesis, male ApoE-/-mice were infused with angiotensin II (AngII, 1000ng/kg/min) for 21days and cotreated with JQ1 (50mg/kg daily) or vehicle control (DMSO). In the in vitro study, we determined the mRNA expression of MMP genes by qPCR and their activity both by the kit and gelatin zymography assay. BET bromodomain inhibition resulted in decreased abdominal aortic diameter (P<0.05) measured by in vivo vascular ultrasound and ex vivo pathologic assessment of aortas. In pursuit of mechanisms for this effect on AAA, we observed that JQ1 treatment led to a downregulation of metalloproteinase gene expression and enzymatic activity both in vitro and in vivo.
  
  
  CONCLUSIONS
  BET bromodomain inhibition improved AAA pathological sequelae, and this effect might be achieved though suppression of MMP genes expression and their activity.
authors.affiliation: Cardiovascular Division, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Duan
authors.affiliation: Cardiovascular Division, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China; Cardiovascular Division, Brigham and Women's Hospital, 77 Ave Louis Pasteur, NRB 742, Boston, MA, United States.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Mao
authors.affiliation: Department of Histology and Embryology, Xiangya School of Medicine, Central South University, 172 Tongzipo Road, Changsha, China.
authors.forename: Chaonan
authors.initials: C
authors.lastname: Liao
authors.affiliation: Cardiovascular Division, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China.
authors.forename: Haoyang
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Cardiovascular Division, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China.
authors.forename: Zelin
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Cardiovascular Division, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Deng
authors.affiliation: Cardiovascular Division, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China.
authors.forename: Qiuning
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, United States.
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.affiliation: Cardiovascular Division, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China.
authors.forename: Guogang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Histology and Embryology, Xiangya School of Medicine, Central South University, 172 Tongzipo Road, Changsha, China. Electronic address: huanghe@csu.edu.cn.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, 77 Ave Louis Pasteur, NRB 742, Boston, MA, United States. Electronic address: jplutzky@rics.bwh.harvard.edu.
authors.forename: Jorge
authors.initials: J
authors.lastname: Plutzky
authors.affiliation: Cardiovascular Division, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China. Electronic address: tianluny@163.com.
authors.forename: Tianlun
authors.initials: T
authors.lastname: Yang
mesh_terms: D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D014230:Triazoles; D000804:Angiotensin II; D012313:RNA; D045726:Metalloproteases
keywords: Aneurysm; BET bromodomain; JQ1; Metalloproteinases