Abstract
Cell apoptosis induced by heat stress is regulated by a complex signaling network. We previously reported that a p53-dependent pathway is involved. Here, we present evidence that NF-κB signaling plays a crucial role in preventing heat stress-induced early apoptosis. Human umbilical vein endothelial cells (HUVECs) were examined and increased phosphorylation of p65 and IκBα were detected, without IκBα degradation. When NF-κB signaling was inhibited by BAY11-7082, or a small interference RNA (siRNA) targeting p65, a significant increase in cell apoptosis and caspase-3 activity was observed, as well as reduced expression and translocation of HSP27 into the nucleus, an accumulation of reactive oxygen species, and prolonged phosphorylation of mitogen-activated protein kinases (MAPKs). In addition, an association between HSP27 and p65 was identified which may enhance NF-κB activation. When HSP27 was overexpressed, pretreatment of HUVECs with the antioxidant, apocynin, or N-acetyl cysteine, suppressed apoptosis. Similarly, inhibition of JNK and p38 with SP600125 and SB203580, respectively, also suppressed apoptosis, whereas siRNA-mediated HSP27 knockdown and treatment with the ERK 1/2 inhibitor PD98059 did otherwise. In conclusion, these findings suggest a novel role for an NF-κB signaling pathway involving HSP27, ROS, and MAPKs that confers a protective effect against heat stress-induced cell apoptosis.
Highlights
The inducers that activate NF-κ B use a common pathway that involves phosphorylation-induced degradation of Iκ B proteins
The transcription factor, NF-κ B, has been shown to be activated during the recovery period following heat stress in HeLa cells[28]. In this study, it was investigated whether heat stress activates NF-κ B in human umbilical vein endothelial cells (HUVECs)
After HUVEC cells were grown in culture media for 48 h, the culture dishes were sealed with parafilm and immersed in a circulating water bath maintained at 43 °C to induce heat stress[29]
Summary
The inducers that activate NF-κ B use a common pathway that involves phosphorylation-induced degradation of Iκ B proteins. NF-κ B has been shown to exert pro-survival functions by inhibiting TNF-α -induced ROS accumulation-mediated prolongation of MAPK activation and necrotic cell death in murine embryonic fibroblasts[18]. Despite these insights, it remains unknown whether ROS play a critical role in heat stress-induced MAPK activation, and whether NF-κ B has a role in mediating oxidative stress and MAPK signaling pathways under physiological conditions in HUVECs. Heat shock proteins (HSPs) are an evolutionarily conserved set of proteins that mediate a cell’s response to heat stress, and a subset of HSPs protects cells against an induction of cell death (including apoptosis and necrosis) in response to a variety of stresses[19]. A novel NF-κ B signaling pathway was identified that includes HSP27 protein expression and translocation into the nucleus, the accumulation of ROS, and subsequent MAPK activation
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