title: Reactive oxygen species mediate heat stress-induced apoptosis via ERK dephosphorylation and Bcl-2 ubiquitination in human umbilical vein endothelial cells.
abstract: Heat stress can induce the mitochondrial apoptotic pathway in HUVEC cells, indicating that apoptosis may be a prominent pathological feature of heat stroke, however, little is known about the precise mechani sms involved in it. In this study, we describe the apoptotic effect of intense heat stress on HUVEC cells and our investigation of its underlying mechanisms. Treatment of cells with intense heat stress induced production of reactive oxygen species (ROS) and a concomitant increase in activation of the mitochondrial apoptotic pathway. Furthermore, by over-expression of MnSOD and GPx in cells, we show that ROS, and especially superoxide, is the primary oxidative species induced by intense heat stress and responsible for cell death. In addition, we explored the mechanism by which superoxide regulates the apoptotic effect of intense heat stress, and found that it involved Bcl-2 down-regulation through ubiquitin - proteasomal degradation. Superoxide production also led to Bcl-2 dephosphorylation through inactivation of MAP kinase ERK1/2, which promoted Bcl-2 ubiquitination. Taken together, these findings describe a novel pathway downstream of heat stress-induced apoptosis in HUVEC cells, and provide new insight into the process of redox-mediated down-regulation of Bcl-2 and apoptosis induction. These results could be important in the understanding of pathogenesis of heat stroke and for the development of preventive and treatment measures, both of which are currently lacking.
authors.affiliation: Department of Intensive Care Unit, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, P.R. China.|Department of Pathophysiology, Southern Medical University, Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Guangzhou 510515, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Epilepsy Surgery, Guangdong Sanjiu Brain Hospital, Guangzhou 510510, P.R. China.|Southern Medical University, Guangzhou, 510515, China.
authors.forename: Hongping
authors.initials: H
authors.lastname: Tan
authors.affiliation: Department of Intensive Care Unit, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, P.R. China.|Department of Pathophysiology, Southern Medical University, Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Guangzhou 510515, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Intensive Care Unit, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, P.R. China.|Department of Pathophysiology, Southern Medical University, Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Guangzhou 510515, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Southern Medical University, Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Guangzhou 510515, P.R. China.
authors.forename: Xuan
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Intensive Care Unit, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510630, P.R. China.|Department of Pathophysiology, Southern Medical University, Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Guangzhou 510515, P.R. China.
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Department of Pathophysiology, Southern Medical University, Guangdong Provincial Key Laboratory of Shock and Microcirculation Research, Guangzhou 510515, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Southern Medical University, Guangzhou, 510515, China.|Department of Intensive Care Unit, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Su
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D042783:Endothelial Cells; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D018869:Heat-Shock Response / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D054875:Ubiquitination; D014471:Umbilical Veins
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Bcl-2; ERK; apoptosis; heat stress; reactive oxygen species