title: NADPH Oxidase/ROS-Dependent VCAM-1 Induction on TNF-α-Challenged Human Cardiac Fibroblasts Enhances Monocyte Adhesion.
abstract: The inflammation-dependent adhesion molecule expressions are characterized in cardiovascular diseases and myocardial tissue infiltrations. Several pro-inflammatory cytokines are elevated in the acute myocardial injury and infarction. Tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine, is raised in the injury tissues and inflammatory regions and involved in the pathogenesis of cardiac injury, inflammation, and apoptosis. In fibroblasts, TNF-α-triggered expression of vascular cell adhesion molecule (VCAM)-1 aggravated the heart inflammation. However, the mechanisms underlying TNF-α-mediated VCAM-1 expression in cardiac fibroblasts remain unclear. Here, the primary cultured human cardiac fibroblasts (HCFs) were used to investigate the effects of TNF-α on VCAM-1 expression. The molecular evidence, including protein, mRNA, and promoter analyses, indicated that TNF-α-induced VCAM-1 gene expression is mediated through the TNFR-dependent manner. Activation of TNF-α/TNFR system triggered PKCα-dependent NADPH oxidase (Nox)/reactive oxygen species (ROS) signal linking to MAPK cascades, and then led to activation of the transcription factor, AP-1. Moreover, the results of mRNA and promoter assay demonstrated that c-Jun/AP-1 phosphorylated by TNF-α turns on VCAM-1 gene expression. Subsequently, up-regulated VCAM-1 on the cell surface of TNF-α-challenged HCFs increased the number of monocytes adhering to these cells. These results indicated that in HCFs, activation of AP-1 by PKCα-dependent Nox/ROS/MAPKs cascades is required for TNF-α-induced VCAM-1 expression. To clarify the mechanisms of TNF-α-induced VCAM-1 expression in HCFs may provide therapeutic strategies for heart injury and inflammatory diseases.
authors: Department of Anesthetics, Chang Gung Memorial Hospital at Linkou, and College of Medicine, Chang Gung University Tao-Yuan, Taiwan.
authors: Chih-Chung
authors: CC
authors: Lin
authors: Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung UniversityTao-Yuan, Taiwan; Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Lin-KouTao-Yuan, Taiwan.
authors: Chien-Chung
authors: CC
authors: Yang
authors: Department of Anesthetics, Chang Gung Memorial Hospital at Linkou, and College of Medicine, Chang Gung University Tao-Yuan, Taiwan.
authors: Chen-Yu
authors: CY
authors: Wang
authors: Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University Tao-Yuan, Taiwan.
authors: Hui-Ching
authors: HC
authors: Tseng
authors: Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University Tao-Yuan, Taiwan.
authors: Chih-Shuo
authors: CS
authors: Pan
authors: Department of Anesthetics, Chang Gung Memorial Hospital at Linkou, and College of Medicine, Chang Gung University Tao-Yuan, Taiwan.
authors: Li-Der
authors: LD
authors: Hsiao
authors: Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung UniversityTao-Yuan, Taiwan; Research Center for Industry of Human Ecology and Graduate Institute of Health Industry Technology, Chang Gung University of Science and TechnologyTao-Yuan, Taiwan.
authors: Chuen-Mao
authors: CM
authors: Yang
keywords: NADPH oxidase; ROS; TNF-α; VCAM-1; cardiac fibroblasts; transcription factor