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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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Homocysteine reduced the release of VEGF and IGF-1 by BMSCs.(a) Homocysteine induced a considerable inhibition of VEGF level in culture medium of BMSCs. (b) IGF-1 level was also obviously decreased by homocysteine in BMSCs. * p<0.05 versus Control.
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pone-0063561-g007: Homocysteine reduced the release of VEGF and IGF-1 by BMSCs.(a) Homocysteine induced a considerable inhibition of VEGF level in culture medium of BMSCs. (b) IGF-1 level was also obviously decreased by homocysteine in BMSCs. * p<0.05 versus Control.

Mentions: We further explore whether homocysteine treatment leads to the changes of BMSCs functions. The VEGF and IGF-1 levels in the culture medium of BMSCs before and after homocysteine treatment were determined by ELISA assay. Figure 7a showed that homocysteine induced a considerable inhibition of VEGF level in culture medium of BMSCs. Likewise, IGF-1 level was also obviously inhibited by homocysteine in BMSCs (Figure 7b). These suggest that the paracrine function of BMSCs was impaired by homocysteine treatment.


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)

Homocysteine reduced the release of VEGF and IGF-1 by BMSCs.(a) Homocysteine induced a considerable inhibition of VEGF level in culture medium of BMSCs. (b) IGF-1 level was also obviously decreased by homocysteine in BMSCs. * p<0.05 versus Control.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0063561-g007: Homocysteine reduced the release of VEGF and IGF-1 by BMSCs.(a) Homocysteine induced a considerable inhibition of VEGF level in culture medium of BMSCs. (b) IGF-1 level was also obviously decreased by homocysteine in BMSCs. * p<0.05 versus Control.
Mentions: We further explore whether homocysteine treatment leads to the changes of BMSCs functions. The VEGF and IGF-1 levels in the culture medium of BMSCs before and after homocysteine treatment were determined by ELISA assay. Figure 7a showed that homocysteine induced a considerable inhibition of VEGF level in culture medium of BMSCs. Likewise, IGF-1 level was also obviously inhibited by homocysteine in BMSCs (Figure 7b). These suggest that the paracrine function of BMSCs was impaired by homocysteine treatment.

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