title: SIRT4 inhibits cigarette smoke extracts-induced mononuclear cell adhesion to human pulmonary microvascular endothelial cells via regulating NF-κB activity.
abstract: Cigarette smoking is an important risk factor for chronic obstructive pulmonary disease (COPD), yet its pathogenic mechanisms are not yet fully understood. Endothelial dysfunction is known to be involved in the pathogenesis of COPD. A detailed understanding of the mechanism involved in its progression would have a substantial impact on the optimization and development of treatment strategies. Here, we report that the expression of SIRT4, a mitochondrial sirtuin, is markedly down-regulated in cigarette smoke extract (CSE)-treated human pulmonary microvascular endothelial cells (HPMECs). Overexpression of SIRT4 significantly inhibits CSE-induced mononuclear cell adhesion to HPMECs. Consistently, we found that overexpression of SIRT4 attenuates the induction of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin. Importantly, SIRT4 was found to negatively regulate CSE-induced NF-κB activation via inhibiting the degradation of IκBα. Moreover, we also found that proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6, the downstream target genes of NF-κB, are also inhibited by overexpression of SIRT4. These results suggest that SIRT4 protects HPMECs exposed to CSE stress via a mechanism that may involve the NF-κB pathway. Strategies based on the enhancement of SIRT4 may prove to be beneficial in the treatment of cigarette smoking caused COPD.
authors.affiliation: Department of Respiratory, Southwest Hospital, Third Military Medical University, China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Respiratory, Southwest Hospital, Third Military Medical University, China.
authors.forename: Haijing
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Respiratory, Southwest Hospital, Third Military Medical University, China.
authors.forename: Guangming
authors.initials: G
authors.lastname: Luo
authors.affiliation: Department of Respiratory, Southwest Hospital, Third Military Medical University, China. Electronic address: xtdai006@hotmail.com.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Dai
mesh_terms: D036002:ADP Ribose Transferases / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D019040:E-Selectin / Q000032:analysis; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology*; D037761:Sirtuins / Q000502:physiology*; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000009:adverse effects*; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
chemical_list: D019040:E-Selectin; C491731:IKBKG protein, human; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D012906:Smoke; D019010:Vascular Cell Adhesion Molecule-1; D036002:ADP Ribose Transferases; D051550:I-kappa B Kinase; C525357:SIRT4 protein, human; D037761:Sirtuins
keywords: Chronic obstructive pulmonary disease; Cigarette smoke extract; Monocyte adhesion; NF-κB; SIRT4