title: Apoptosis of bone marrow mesenchymal stem cells caused by homocysteine via activating JNK signal.
abstract: Bone marrow mesenchymal stem cells (BMSCs) are capable of homing to and repair damaged myocardial tissues. Apoptosis of BMSCs in response to various pathological stimuli leads to the attenuation of healing ability of BMSCs. Plenty of evidence has shown that elevated homocysteine level is a novel independent risk factor of cardiovascular diseases. The present study was aimed to investigate whether homocysteine may induce apoptosis of BMSCs and its underlying mechanisms. Here we uncovered that homocysteine significantly inhibited the cellular viability of BMSCs. Furthermore, TUNEL, AO/EB, Hoechst 333342 and Live/Death staining demonstrated the apoptotic morphological appearance of BMSCs after homocysteine treatment. A distinct increase of ROS level was also observed in homocysteine-treated BMSCs. The blockage of ROS by DMTU and NAC prevented the apoptosis of BMSCs induced by homocysteine, indicating ROS was involved in the apoptosis of BMSCs. Moreover, homocysteine also caused the depolarization of mitochondrial membrane potential of BMSCs. Furthermore, apoptotic appearance and mitochondrial membrane potential depolarization in homocysteine-treated BMSCs was significantly reversed by JNK inhibitor but not p38 MAPK and ERK inhibitors. Western blot also confirmed that p-JNK was significantly activated after exposing BMSCs to homocysteine. Homocysteine treatment caused a significant reduction of BMSCs-secreted VEGF and IGF-1 in the culture medium. Collectively, elevated homocysteine induced the apoptosis of BMSCs via ROS-induced the activation of JNK signal, which provides more insight into the molecular mechanisms of hyperhomocysteinemia-related cardiovascular diseases.
authors.affiliation: Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Benzhi
authors.initials: B
authors.lastname: Cai
authors.forename: Xingda
authors.initials: X
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Yanju
authors.initials: Y
authors.lastname: Liu
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Hongyang
authors.initials: H
authors.lastname: Chen
authors.forename: Kun
authors.initials: K
authors.lastname: Yin
authors.forename: Xueying
authors.initials: X
authors.lastname: Tan
authors.forename: Jiuxin
authors.initials: J
authors.lastname: Zhu
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Pan
authors.forename: Baoqiu
authors.initials: B
authors.lastname: Wang
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006710:Homocysteine / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D006710:Homocysteine; D007334:Insulin-Like Growth Factor I; D048031:JNK Mitogen-Activated Protein Kinases