title: Gene silencing of TACE enhances plaque stability and improves vascular remodeling in a rabbit model of atherosclerosis.
abstract: We aimed to test the hypothesis that gene silencing of tumor necrosis factor alpha converting enzyme (TACE) may attenuate lesion inflammation and positive vascular remodeling and enhance plaque stability in a rabbit model of atherosclerosis. Lentivirus-mediated TACE shRNA was injected into the abdominal aortic plaques of rabbits which effectively down-regulated TACE expression and activities from week 8 to week 16. TACE gene silencing reduced remodeling index and plaque burden, and diminished the content of macrophages and lipids while increased that of smooth muscle cells and collagen in the aortic plaques. In addition, TACE gene silencing attenuated the local expression of P65, iNOS, ICAM-1, VEGF and Flt-1 and activities of MMP9 and MMP2 while increased the local expression of TGF-β1 together with reduced number of neovessels in the aorta. TACE shRNA treatment resulted in down-regulated expression of TACE in macrophages and blunted ERK-P38 phosphorylation and tube formation of co-cultured mouse vascular smooth muscle cells or human umbilical vein endothelial cells. In conclusion, gene silencing of TACE enhanced plaque stability and improved vascular positive remodeling. The mechanisms may involve attenuated local inflammation, neovascularization and MMP activation, as well as enhanced collagen production probably via down-regulated ERK-NF-κB and up-regulated TGF-β1 signaling pathways.
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and the State-Province Co-cultivated Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.|Department of Cardiology, Qianfoshan Hospital of Shandong Province, Jinan, Shandong 250014, China.
authors.forename: Xueqiang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and the State-Province Co-cultivated Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Kong
authors.affiliation: Department of Traditional Chinese Medicine, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and the State-Province Co-cultivated Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
authors.forename: Xuping
authors.initials: X
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and the State-Province Co-cultivated Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
authors.forename: Peili
authors.initials: P
authors.lastname: Bu
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and the State-Province Co-cultivated Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and the State-Province Co-cultivated Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000072198:ADAM17 Protein; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015415:Biomarkers; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000097:blood; D008055:Lipids / Q000097:blood; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011817:Rabbits; D066253:Vascular Remodeling / Q000235:genetics*
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; D008055:Lipids; D034741:RNA, Small Interfering; D003094:Collagen; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; D020778:Matrix Metalloproteinase 2; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse