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.
Highlights
Heat stroke is a severely life-threatening heatrelated illness, characterized by a rapid rise in core body temperature to greater than 40°C, and central nervous system dysfunction, such as delirium, convulsions, or coma [1,2,3]
Cells were harvested at 0,1,3,6 and 9h after 2h of heat stress (43°C), and cell viability declined significantly after heat stress in a time-dependent manner. These results suggest that heat stress exerts a cytotoxic effect on Human umbilical vein endothelial cells (HUVECs) cells
reactive oxygen species (ROS) involved in the mitochondrial apoptotic pathway is induced by intense heat stress in HUVEC cells
Summary
Heat stroke is a severely life-threatening heatrelated illness, characterized by a rapid rise in core body temperature to greater than 40°C, and central nervous system dysfunction, such as delirium, convulsions, or coma [1,2,3]. Accumulating evidence proves that high heat can stimulate cell death and tissue injury, and that apoptosis plays a key role during this process. Both in vitro and in vivo studies have demonstrated that elevated temperatures can result in direct injury to vascular endothelium, indicating that targeted endothelial cell damage may be the underlying cause of prominent heatstroke features [5,6,7,8]. It has been observed that acute heat stress-induced endothelial cell damage results in apoptosis [4, 9], suggesting that apoptotic death of endothelial cells might be a critical event in the pathogenesis of heat stroke In light of these findings, the molecular mechanisms of endothelial cell apoptosis induced by heat stress require further study
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