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Apoptosis of bone marrow mesenchymal stem cells caused by homocysteine via activating JNK signal.

Cai B, Li X, Wang Y, Liu Y, Yang F, Chen H, Yin K, Tan X, Zhu J, Pan Z, Wang B, Lu Y - PLoS ONE (2013)

Bottom Line: Apoptosis of BMSCs in response to various pathological stimuli leads to the attenuation of healing ability 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.Homocysteine treatment caused a significant reduction of BMSCs-secreted VEGF and IGF-1 in the culture medium.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Harbin Medical University, Harbin, Heilongjiang Province, China.

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.

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JNK signal is involved in the apoptosis of BMSCs induced by homocysteine.JNK specific inhibitor effectively attenuated the apoptosis induced by homocysteine 300 µM in BMSCs. However, p38 and ERK specific inhibitors did not affect homocysteine-induced apoptotic morphological changes in BMSCs.
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pone-0063561-g005: JNK signal is involved in the apoptosis of BMSCs induced by homocysteine.JNK specific inhibitor effectively attenuated the apoptosis induced by homocysteine 300 µM in BMSCs. However, p38 and ERK specific inhibitors did not affect homocysteine-induced apoptotic morphological changes in BMSCs.

Mentions: A large body of evidence has shown that MAPK signal pathway is involved in ROS-mediated cellular apoptosis [26]. However, whether MAPK signal pathway also plays a critical role in homocysteine-induced BMSCs apoptosis remain unknown. Here, we found that the specific JNK inhibitor, SP600125 (10 µM) could reverse homocysteine-induced BMSCs apoptosis featured by the inhibition of mitochondrial membrane potential depolarization and nucleus damage, without the impact on intracellular ROS level (Figure 5). Neither p38 MAKP inhibitor SB203580 (5 µM) nor ERK inhibitor PD98059 (25 µM) is able to reverse homocysteine-induced apoptotic morphological changes. These results indicate that JNK signal pathway is required for homocysteine-induced BMSCs apoptosis.


Apoptosis of bone marrow mesenchymal stem cells caused by homocysteine via activating JNK signal.

Cai B, Li X, Wang Y, Liu Y, Yang F, Chen H, Yin K, Tan X, Zhu J, Pan Z, Wang B, Lu Y - PLoS ONE (2013)

JNK signal is involved in the apoptosis of BMSCs induced by homocysteine.JNK specific inhibitor effectively attenuated the apoptosis induced by homocysteine 300 µM in BMSCs. However, p38 and ERK specific inhibitors did not affect homocysteine-induced apoptotic morphological changes in BMSCs.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3646804&req=5

pone-0063561-g005: JNK signal is involved in the apoptosis of BMSCs induced by homocysteine.JNK specific inhibitor effectively attenuated the apoptosis induced by homocysteine 300 µM in BMSCs. However, p38 and ERK specific inhibitors did not affect homocysteine-induced apoptotic morphological changes in BMSCs.
Mentions: A large body of evidence has shown that MAPK signal pathway is involved in ROS-mediated cellular apoptosis [26]. However, whether MAPK signal pathway also plays a critical role in homocysteine-induced BMSCs apoptosis remain unknown. Here, we found that the specific JNK inhibitor, SP600125 (10 µM) could reverse homocysteine-induced BMSCs apoptosis featured by the inhibition of mitochondrial membrane potential depolarization and nucleus damage, without the impact on intracellular ROS level (Figure 5). Neither p38 MAKP inhibitor SB203580 (5 µM) nor ERK inhibitor PD98059 (25 µM) is able to reverse homocysteine-induced apoptotic morphological changes. These results indicate that JNK signal pathway is required for homocysteine-induced BMSCs apoptosis.

Bottom Line: Apoptosis of BMSCs in response to various pathological stimuli leads to the attenuation of healing ability 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.Homocysteine treatment caused a significant reduction of BMSCs-secreted VEGF and IGF-1 in the culture medium.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Harbin Medical University, Harbin, Heilongjiang Province, China.

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.

Show MeSH
Related in: MedlinePlus