Qiong Duan1, Xiaoxiao Mao2, Chaonan Liao3, Haoyang Zhou1, Zelin Sun1, Xu Deng1, Qiuning Hu1, Jun Qi4, Guogang Zhang1, He Huang5, Jorge Plutzky6, Tianlun Yang7. 1. Cardiovascular Division, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China. 2. 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. 3. Department of Histology and Embryology, Xiangya School of Medicine, Central South University, 172 Tongzipo Road, Changsha, China. 4. Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, United States. 5. Department of Histology and Embryology, Xiangya School of Medicine, Central South University, 172 Tongzipo Road, Changsha, China. Electronic address: huanghe@csu.edu.cn. 6. Cardiovascular Division, Brigham and Women's Hospital, 77 Ave Louis Pasteur, NRB 742, Boston, MA, United States. Electronic address: jplutzky@rics.bwh.harvard.edu. 7. Cardiovascular Division, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China. Electronic address: tianluny@163.com.
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. METHODS AND 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.
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. METHODS AND 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: Laura M Tsujikawa; Li Fu; Shovon Das; Christopher Halliday; Brooke D Rakai; Stephanie C Stotz; Christopher D Sarsons; Dean Gilham; Emily Daze; Sylwia Wasiak; Deborah Studer; Kristina D Rinker; Michael Sweeney; Jan O Johansson; Norman C W Wong; Ewelina Kulikowski Journal: Clin Epigenetics Date: 2019-07-12 Impact factor: 6.551