title: Andrographolide inhibits nuclear factor-κB activation through JNK-Akt-p65 signaling cascade in tumor necrosis factor-α-stimulated vascular smooth muscle cells.
abstract: Critical vascular inflammation leads to vascular dysfunction and cardiovascular diseases, including abdominal aortic aneurysms, hypertension, and atherosclerosis. Andrographolide is the most active and critical constituent isolated from the leaves of Andrographis paniculata, a herbal medicine widely used for treating anti-inflammation in Asia. In this study, we investigated the mechanisms of the inhibitory effects of andrographolide in vascular smooth muscle cells (VSMCs) exposed to a proinflammatory stimulus, tumor necrosis factor-α (TNF-α). Treating TNF-α-stimulated VSMCs with andrographolide suppressed the expression of inducible nitric oxide synthase in a concentration-dependent manner. A reduction in TNF-α-induced c-Jun N-terminal kinase (JNK), Akt, and p65 phosphorylation was observed in andrographolide-treated VSMCs. However, andrographolide affected neither IκBα degradation nor p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 phosphorylation under these conditions. Both treatment with LY294002, a phosphatidylinositol 3-kinase/Akt inhibitor, and treatment with SP600125, a JNK inhibitor, markedly reversed the andrographolide-mediated inhibition of p65 phosphorylation. In addition, LY294002 and SP600125 both diminished Akt phosphorylation, whereas LY294002 had no effects on JNK phosphorylation. These results collectively suggest that therapeutic interventions using andrographolide can benefit the treatment of vascular inflammatory diseases, and andrographolide-mediated inhibition of NF-κB activity in TNF-α-stimulated VSMCs occurs through the JNK-Akt-p65 signaling cascade, an IκBα-independent mechanism.
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Yu-Ying
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Ming-Jen
authors.identifier: 0000-0001-9688-8494
authors.initials: MJ
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan ; Department of Pharmacology, School of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Hsieh
authors.affiliation: Department of Microbiology and Immunology, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Lin-Wen
authors.initials: LW
authors.lastname: Lee
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan ; Department of Pharmacology, School of Medicine, Taipei Medical University, Taipei 11031, Taiwan ; Department of Cardiology, Chi-Mei Medical Center, Tainan City 71004, Taiwan ; Department of Pharmacy, Chia Nan University of Pharmacy & Science, Tainan City 71004, Taiwan.
authors.forename: Zhih-Cherng
authors.identifier: 0000-0002-3265-5218
authors.initials: ZC
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan ; Department of Pharmacology, School of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Joen-Rong
authors.initials: JR
authors.lastname: Sheu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004224:Diterpenes / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004224:Diterpenes; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C030419:andrographolide; D052247:Nitric Oxide Synthase Type II; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases