Author + information
- JIan Zhang1,
- Tian Xiaoxiang1,
- Yan Chenghui1,
- Zhang Xiaolin1,
- Kang Jian1,
- Han Yaling1 and
- Wang Shuang1
Cellular repressor of E1A-stimulated genes (CREG) has been found to enhance differentiation and/or reduces cell proliferation. The potential therapeutic role of embryonic stem cells (ESCs) in ischemic heart disease is subject to intense investigation. In our studies, we induced myocardial infarct (MI) in mouse model, and monitored the effects of ESCs transplantation of overexpression of CREG on cardiac function.
Mouse MI model was established by ligation of coronary artery. Embryonic stem cells (ESCs) with CREG overexpression (wtCREG) or with EGFP expression were transplanted into peri-infarction area. Injection of DMEM served as control. All the mice were analyzed for hemodynamic and pathologic parameters 1 month after MI and injection.
The ratio of heart/body weight, heart/tibia length in wtCREG group was decreased at day 28 compared with EGFP, while DMEM group had the highest ratio. TTC analysis showed the smallest infarct size in wtCREG group. Hemodynamic assessment by Millar catheterization demonstrated a significant increase in +dP/dt and –dP/dt, as well as a significant drop of LVEDP at 28 days after MI. Animals transplanted with EGFP-ESCs also showed a significant improvement of these cardiac functional parameters, as compared with those injected with DMEM. The wtCREG group had a significantly greater decrease in end-diastolic and end-systolic dimensions in comparison with DMEM and EGFP animals, reflecting decelerated dilative remodeling in the wtCREG. This was associated with marked LV function improvement as reflected by increased LVEF and LVFS. Both myocardial fibrosis and cardiomyocyte apoptosis were significantly reduced in wtCREG. Over-expression of CREG (wtCREG ESCs) decreased ASK1 protein level by 48%. Upon elevation of CREG levels, also decreased JNK1/2 and p38 expression levels in the cardiomyocytes. We also found increased bax and decreased bcl-2 expression at 2 weeks post-MI.
Transplantation of CREG modified significantly improves cardiac function and reduces fibrosis by inhibiting apoptosis of cardiomyocytes.