title: Tongxinluo inhibits neointimal formation by regulating the expression and post-translational modification of KLF5 in macrophages.
abstract: Neointimal hyperplasia is a common pathological characteristic in diverse vascular remodeling diseases. The inflammatory response that follows vascular injury plays an important role in intimal hyperplasia. Tongxinluo (TXL), a traditional Chinese medicine, can ameliorate neointimal formation via suppressing vascular inflammatory response induced by vascular injury. However, the mechanisms underlying anti-inflammatory and anti-intimal hyperplasia of TXL are still not fully understood. The aim of present study was to examine whether the expression and post-translational modification of KLF5 were involved in the vasoprotective effects of TXL. In vivo, TXL inhibited neointimal formation induced by carotid artery injury. In vitro, TNF-α treatment of macrophages resulted in the increased proliferation and migration, but the effects of TNF-α on macrophages were blocked by TXL treatment. Next, KLF5 expression was up-regulated by carotid artery injury in vivo, as well as by exposure of macrophages to TNF-α in vitro, whereas TXL treatment abrogated the up-regulation of KLF5 by TNF-α or vascular injury. Intimal hyperplasia was strongly reduced in macrophage-specific KLF5 knockout (KLF5ly-/-) mice, indicating that TXL inhibits intimal hyperplasia by suppression of KLF5 expression. Furthermore, besides down-regulating KLF5 expression in macrophages, TXL also regulated KLF5 stability by ubiquitination and sumoylation of KLF5. Finally, TNF-α induced KLF5 sumoylation via PI3K/Akt signaling, whereas TXL inhibited Akt phosphorylation induced by TNF-α. We conclude that the multiple ingredients in TXL may act on different targets, which in turn generates a range of actions that manifest as a comprehensively vasoprotective effect.
authors.affiliation: Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University Shijiazhuang 050017, PR China.
authors.forename: Wen
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University Shijiazhuang 050017, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University Shijiazhuang 050017, PR China.
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University Shijiazhuang 050017, PR China.
authors.forename: Ling-Yan
authors.initials: LY
authors.lastname: Yue
authors.affiliation: Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University Shijiazhuang 050017, PR China.
authors.forename: Chan
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University Shijiazhuang 050017, PR China.
authors.forename: Dong
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University Shijiazhuang 050017, PR China.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University Shijiazhuang 050017, PR China.
authors.forename: Jin-Kun
authors.initials: JK
authors.lastname: Wen
keywords: KLF5; Tongxinluo; inflammation; intimal hyperplasia; sumoylation; ubiquitination