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Calcium sensing receptor involving in therapy of embryonic stem cell transplantation alleviates acute myocardial infarction by inhibiting apoptosis and oxidative stress in rats - PubMed

Calcium sensing receptor involving in therapy of embryonic stem cell transplantation alleviates acute myocardial infarction by inhibiting apoptosis and oxidative stress in rats

Hui Yuan et al. Iran J Basic Med Sci. 2020 Oct.

Abstract

Objectives: The aims of the present study were to investigate the expression of calcium sensing receptor (CaSR) at different times in acute myocardial infarction (AMI) rat myocardial tissue after mouse embryonic stem cells (mESCs) transplantation treatment and to assess its effects on apoptosis and oxidative stress of cardiomyocytes.

Materials and methods: The AMI rats were treated with mESCs, Calindol (a CaSR agonist) and Calhex231 (a CaSR inhibitor). Serum measurements, Echocardiographic analysis and TUNEL assay were performed. Myocardial ultrastructure changes were viewed by electron microscopy. Additionally, western blotting was used to detect the protein expressions.

Results: Compared to the sham group, it was found that the expression levels of CaSR, caspase-3, cytoplasmic cytochrome C (cyt-C) and Bcl2-associated x (Bax), and the levels of Malondialdehyde (MDA) were significantly increased in both AMI and AMI + mESCs + Calindol groups with the development of myocardial infarction. Furthermore, the ultra-microstructure of cardiomyocyte was highly damaged, the expression levels of mitochondrial cyt-C and B-cell lymphoma 2 (Bcl-2) were significantly decreased, and there was decreased activity of superoxide dismutase (SOD). However, the combination of Calhex231 and mESCs transplantation could inhibit these changes.

Conclusion: Our results suggested that CaSR expression in myocardial tissue of AMI rats was increased over time, and that Calhex231 could enhance the efficacy of ESCs transplantation for the treatment of AMI, which would be a new therapeutic strategy for the treatment of AMI.

Keywords: Acute myocardial infarction; Apoptosis; Calcium sensing receptor; Cell transplantation; Embryonic stem cell.

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Figures

Figure 1
Figure 1

Successful modeling of AMI and oxidative stress indexes in serum. (A) CK, LDH and cTnT levels in serum (B) MDA and SOD levels in serum. *P<0.05 vs. Sham (n=5). #P<0.05 vs. AMI group. P<0.05 vs. Calindol-treated group. CK: creatine kinase, LDH: lactate dehydrogenase, cTnT: cardiac troponin T, MDA: malondialdehyde, SOD: superoxide dismutase, AMI: acute myocardial infarction

Figure 2
Figure 2

Ultrastructural changes of myocardial tissue detected by electron microscope. Magnification, x15000

Figure 3
Figure 3

Changes in protein expression levels were detected by western blotting after AMI from week 1 to week 4. *P<0.05 vs. sham group. #P<0.05 vs. AMI group. P<0.05 vs. Calindol Hydrochloride-treated group. P<0.05 vs. mESC transplantation group (n=3). AMI: acute myocardial infarction, mESCs: mouse embryonic stem cells

Figure 4
Figure 4

Changes of cardiac function in different group, and the effects of AMI treated with mESCs transplantation + Calhex231 at 1st, 2nd and 4th weeks

Figure 5
Figure 5

Detection of apoptosis in rat myocardial tissue by TUNEL staining. (A) Nuclei of TUNEL positive cells were brown. (B) Statistical analysis of apoptosis indexes at weeks 1, 2 and 4 in each group; Magnification, x400. *P<0.05 vs. sham group. #P<0.05 vs. AMI group. P<0.05 vs. Calindol-treated group. P<0.05 vs. 1st week (n=5). AMI: acute myocardial infarction

Figure 6
Figure 6

Expression of apoptotic-related proteins and cytoplasmic/mitochondrial cyt-C detected by western blotting. (A-C) Protein expression levels of cytoplasmic cyt-C, Bax and caspase-3 in the myocardial tissue of AMI rats were detected by western blotting at weeks 1, 2 and 4 in each group, respectively. *P<0.05 vs. sham group. #P<0.05 vs. AMI group. P<0.05 vs. Calindol-treated group. P<0.05 vs. mESCs transplantation group (n=3). AMI: acute myocardial infarction, mESCs: mouse embryonic stem cells

Figure 7
Figure 7

Schematic diagram illustrating the therapeutic acute myocardial infarction mechanism of Calhex231 combining with embryonic stem cell transplantation

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