title: Andrographolide induces vascular smooth muscle cell apoptosis through a SHP-1-PP2A-p38MAPK-p53 cascade.
abstract: The abnormal growth of vascular smooth muscle cells (VSMCs) is considered a critical pathogenic process in inflammatory vascular diseases. We have previously demonstrated that protein phosphatase 2 A (PP2A)-mediated NF-κB dephosphorylation contributes to the anti-inflammatory properties of andrographolide, a novel NF-κB inhibitor. In this study, we investigated whether andrographolide causes apoptosis, and characterized its apoptotic mechanisms in rat VSMCs. Andrographolide activated the p38 mitogen-activated protein kinase (p38MAPK), leading to p53 phosphorylation. Phosphorylated p53 subsequently transactivated the expression of Bax, a pro-apoptotic protein. Transfection with pp2a small interfering RNA (siRNA) suppressed andrographolide-induced p38MAPK activation, p53 phosphorylation, and caspase 3 activation. Andrographolide also activated the Src homology 1 domain-containing protein tyrosine phosphatase (SHP-1), and induced PP2A dephosphorylation, both of which were inhibited by the SHP-1 inhibitor sodium stibogluconate (SSG) or shp-1 siRNA. SSG or shp-1 siRNA prevented andrographolide-induced apoptosis. These results suggest that andrographolide activates the PP2A-p38MAPK-p53-Bax cascade, causing mitochondrial dysfunction and VSMC death through an SHP-1-dependent mechanism.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Thanasekaran
authors.initials: T
authors.lastname: Jayakumar
authors.affiliation: Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Kuan-Hung
authors.initials: KH
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, School of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Duen-Suey
authors.initials: DS
authors.lastname: Chou
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wan-Jung
authors.initials: WJ
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, School of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Hsu
authors.affiliation: 1] Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan [2] Department of Pharmacology, School of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Joen-Rong
authors.initials: JR
authors.lastname: Sheu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D005260:Female; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D004224:Diterpenes; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; C030419:andrographolide; D048051:p38 Mitogen-Activated Protein Kinases; C514014:Ppp2ca protein, rat; D054648:Protein Phosphatase 2; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509250:Ptpn6 protein, rat; D053148:Caspase 3