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.
Highlights
Over the past decades, cardiovascular diseases remain a leading cause of mortality all over the word
The cellular viability of Bone marrow mesenchymal stem cells (BMSCs) were significantly decreased by homocysteine 100, 300 and 1000 mM to 85.5964.69%, 82.8264.08% and 69.2769.97 after treatment for 24 h, respectively, but it was not altered by homocysteine 30 mM after treatment for 24 h (Figure 1b)
Though the cellular viability of BMSCs was decreased by homocysteine, MTT can not represent the apoptosis of BMSCs induced by homocysteine
Summary
Cardiovascular diseases remain a leading cause of mortality all over the word. Though the therapeutic advances have improved the survival of patients with cardiovascular diseases in clinics, the loss of cardiac cells due to apoptosis or necrosis in injured hearts can not be reversed. After stimulated by inflammatory and cytokines such as stromal cell-derived factor-1 (SDF-1), BMSCs was shown to enter the circulating blood and migrate to the injured hearts [5,6], which enable BMSCs to regenerate the myocardium by transdifferentiation, neovascularization and paracrine actions [7,8,9]. Several studies have displayed only modest or even low levels of local retention, survival, and differentiation of BMSCs into cardiac cells under ischemic and inflammatory injury [12,13,14,15]. On the contrary, preconditioning of BMSCs with hypoxia or some chemicals enhanced its resistance to these damaged factors and protected BMSCs against apoptosis [15,16]
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