PAR1‑mediated c‑Jun activation promotes heat stress‑induced early stage apoptosis of human umbilical vein endothelial cells.

Abstract

Our previous study indicated that when human umbilical vein endothelial cells (HUVECs), which are involved in endothelial barrier function, are heat stressed, levels of protease‑activated receptor 1 (PAR1) are increased significantly. In the present study, it was demonstrated that PAR1 serves a vital role in heat stress‑induced HUVEC apoptosis. When the PAR1 inhibitor, SCH79797 (SCH), or a small interfering RNA (siRNA) targeting PAR1 were used to inhibit PAR1 signaling, a marked decrease in cell apoptosis, caspase‑3 activity and the expression of the pro‑apoptotic protein B‑cell lymphoma 2 (Bcl‑2) associated X (Bax), as well as increased expression of the anti‑apoptotic Bcl‑2 family member, myeloid cell leukemia 1 (Mcl‑1), were observed. In addition, heat stress‑induced apoptosis, caspase‑3 activity and the expression of Bax were significantly increased following administration of the PAR1 agonist, TFLLR‑NH2 or adenovirus overexpression of PAR1. This was accompanied by decreased protein expression levels of Mcl‑1. Furthermore, it was identified that the DNA binding activity of the nuclear factor (NF)‑κB p65 subunit increased and c‑Jun activation was reduced as a result of inhibition of PAR1 signaling by SCH or siRNA‑mediated PAR1 knockdown in heat stress‑induced HUVECs. Additionally, our previous study reported that NF‑κB p65 activation may have an anti‑apoptosis effect on heat stressed HUVECs, whereas in the present study c‑Jun activation had a pro‑apoptosis effect on heat stressed HUVECs. Taken together, these results indicated that PAR1 signaling‑mediated c‑Jun activation promotes early apoptosis of HUVEC cells induced by heat stress.

• Authors: Shuang Zhang, Yanan Liu, Zhenglian Wang, Jingxian Liu, Zhengtao Gu, Qiulin Xu, Lei Su
• Journal: Molecular medicine reports (Mol Med Rep) Vol. 15 Issue 5 Pg. 2595-2603 (May 2017) ISSN: 1791-3004 [Electronic] Greece
• PMID: 28447716 (Publication Type: Journal Article)

Chemical References

• BAX protein, human
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine
• Proto-Oncogene Proteins c-jun
• Pyrroles
• Quinazolines
• RELA protein, human
• Receptor, PAR-1
• Transcription Factor RelA
• bcl-2-Associated X Protein
• CASP3 protein, human
• Caspase 3

Topics

• Apoptosis (drug effects, physiology)
• Caspase 3 (genetics, metabolism)
• Heat-Shock Response (physiology)
• Human Umbilical Vein Endothelial Cells
• Humans
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Proto-Oncogene Proteins c-jun (genetics, metabolism)
• Pyrroles (pharmacology)
• Quinazolines (pharmacology)
• Receptor, PAR-1 (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects, physiology)
• Transcription Factor RelA (genetics, metabolism)
• bcl-2-Associated X Protein (genetics, metabolism)