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Abstract
Heat stroke has increased in frequency worldwide in recent years and continues to have a high morbidity and mortality. Identification of the mechanisms mediating heat stoke is important and necessary. Our preliminary study revealed heat stress (HS)-induced apoptosis of vascular endothelial cells was associated with reactive oxygen species (ROS)-induced p53 translocation into mitochondria. Previous studies have suggested the prolyl-isomerase Pin1 regulates p53 functioning through specific binding to p53 phosphorylation sites. Based on these studies, we presumed Pin1 is a key intermediate in regulation of mitochondrial p53 translocation through a HS-induced ROS-p53 transcription-independent apoptosis pathway. In this context, we revealed p53 had a crucial role in a HS-induced mitochondrial apoptotic pathway, where p53 protein rapidly translocated into mitochondria in endothelial cells both in vitro and in vivo. In particular, HS caused an increase in p53 phosphorylation at Ser46 that facilitated interactions with phosphorylation-dependent prolyl-isomerase Pin1, which has a key role in promoting HS-induced localization of p53 to mitochondria. Furthermore, we also found ROS production was a critical mediator in HS-induced Pin1/p53 signaling and was involved in regulating mitochondrial apoptosis pathway activation. Therefore, we have contributed to our profound understanding of the mechanism underlying HS-induced endothelial dysfunction in an effort to reduce the mortality and morbidity of heat stroke.
Highlights
The intensity, frequency, and duration of heat waves have increased, especially over the past decades due to the changing climate and, it is feared that the number of patients with heat-associated illnesses may continue to increase[1,2,3]
We previously demonstrated that reactive oxygen species (ROS) are involved in the signaling events that lead to mitochondrial translocation of p53 in human umbilical vein endothelial cells (HUVECs)[9,10]
Our work indicates that, during heat stress (HS)-induced apoptosis of HUVECs, mitochondrial translocation of p53 is involved in triggering of ROS-dependent apoptosis
Summary
The intensity, frequency, and duration of heat waves have increased, especially over the past decades due to the changing climate and, it is feared that the number of patients with heat-associated illnesses may continue to increase[1,2,3]. Li et al Cell Death and Disease (2019)10:96 involved in heat stroke pathogenesis, the associated mechanisms need to be further delineated. Due to the complexity of the intracellular functions of p53, a deeper understanding of the convergence of signaling networks at this hub mediating HS-dependent toxicity is needed to characterize the reduction in vascular endothelial cell survival during HS. We previously demonstrated that reactive oxygen species (ROS) are involved in the signaling events that lead to mitochondrial translocation of p53 in human umbilical vein endothelial cells (HUVECs)[9,10]. Our work indicates that, during HS-induced apoptosis of HUVECs, mitochondrial translocation of p53 is involved in triggering of ROS-dependent apoptosis. The precise mechanism by which HS leads to apoptosis of vascular endothelial cells remains largely unclear
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