Calcium-sensing receptor-mediated mitogen-activated protein kinase pathway improves the status of transplanted mouse embryonic stem cells in rats with acute myocardial infarction
- 309 Downloads
Several studies have identified the critical role of calcium-sensing receptors (CaSRs) in cardiac ischaemia/reperfusion injury and cardiac hypertrophy and have demonstrated that CaSRs induce myocardial apoptosis by activating MAPKs. Using acute myocardial infarction rat models, we found that a combination therapy of CaSR inhibition and embryonic stem cell (ESC) transplantation after acute myocardial infarction (AMI) leads to a dramatic reduction in the infarct size; a significant increase in the maximum rising and falling rate (+dp/dtmax and −dp/dtmax, respectively) of left ventricular pressure; a significant decrease in left ventricular end-diastolic pressure; a significant decrease in the mRNA expression level of CaSR, Bax, Bcl-2, cleaved caspase-3, cleaved caspase-9, p-ERK, p-JNK and p-P38 protein together with apoptosis indexes in the C and E groups; and a significant decrease in cTnT levels as well as LDH and CK activity. These findings indicate that cardiac function could be enhanced significantly by combination therapy with CaSR inhibition and ESC transplantation; the effect was better than ESC transplantation alone, and the mechanism might be associated with a reduction in cell apoptosis via the inhibition of the MAPK pathway. Apoptosis could be reduced through CaSR, which regulates the MAPK pathway and apoptosis-related protein. Our study indicated that CaSR inhibitors have a pivotal role in the treatment of AMI.
KeywordsCalcium-sensing receptor Embryonic stem cells Acute myocardial infarction Cardiac function Cellular transplant
This work was supported by the National Natural Science Foundation of China (No. 81300163, 81200160).
- 1.Chen YL, Sun CK, Tsai TH, Chang LT, Leu S, Zhen YY, Sheu JJ, Chua S, Yeh KH, Lu HI, Chang HW, Lee FY, Yip HK (2015) Adipose-derived mesenchymal stem cells embedded in platelet-rich fibrin scaffolds promote angiogenesis, preserve heart function, and reduce left ventricular remodeling in rat acute myocardial infarction. Am J Transl Res 7(5):781PubMedPubMedCentralGoogle Scholar
- 3.Zhang GW, Gu TX, Guan XY, Sun XJ, Qi X, Li XY, Wang XB, Yu L, Jiang DQ, Tang R, Li-Ling J (2015) bFGF binding cardiac extracellular matrix promotes the repair potential of bone marrow mesenchymal stem cells in a rabbit model for acute myocardial infarction. Biomed Mater 10(6):065018CrossRefPubMedGoogle Scholar
- 4.Lee HW, Lee HC, Park JH, Kim BW, Ahn J, Kim JH, Park JS, Oh JH, Choi JH, Cha KS, Hong TJ, Park TS, Kim SP, Song S, Kim JY, Park MH, Jung JS (2015) Effects of intracoronary administration of autologous adipose tissue-derived stem cells on acute myocardialinfarction in a porcine model. Yonsei Med J 56(6):1522–1529CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Wang LN, Wang C, Lin Y, Xi YH, Zhang WH, Zhao YJ, Li HZ, Tian Y, Lv YJ, Yang BF, Xu CQ (2008) Involvement of calcium-sensing receptor in cardiachypertrophy-induced by angiotensin II through calcineurin pathway in cultured neonatal rat cardiomyocytes. Biochem Biophys Res Commun 369(2):584–589CrossRefPubMedGoogle Scholar
- 9.Lu FH, Fu SB, Leng X, Zhang X, Dong S, Zhao YJ, Ren H, Li H, Zhong X, Xu CQ, Zhang WH (2013) Role of the calcium-sensing receptor in cardiomyocyte apoptosis via the sarcoplasmic reticulum and mitochondrial death pathway in cardiac hypertrophy and heart failure. Cell Physiol Biochem 31(4–5):728–743CrossRefPubMedGoogle Scholar
- 12.Huber BC, Ransohoff JD, Ransohoff KJ, Riegler J, Ebert A, Kodo K, Gong Y, Sanchez-Freire V, Dey D, Kooreman NG, Diecke S, Zhang WY, Odegaard J, Hu S, Gold JD, Robbins RC, Wu JC (2013) Costimulation-adhesion blockade is superior to cyclosporine A and prednisone immunosuppressive therapyfor preventing rejection of differentiated human embryonic stem cells following transplantation. Stem Cells 31(11):2354–2363CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Mummery C, Ward-van Oostwaard D, Doevendans P, Spijker R, van den Brink S, Hassink R, van der Heyden M, Opthof T, Pera M, de la Riviere AB, Passier R, Tertoolen L (2003) Differentiation of human embryonic stem cells to cardiomyocytes: role of coculture with visceral endoderm-likecells. Circulation 107(21):2733–2740CrossRefPubMedGoogle Scholar
- 18.Kuethe F, Figulla HR, Voth M, Richartz BM, Opfermann T, Sayer HG, Krack A, Fritzenwanger M, Höffken K, Gottschild D, Werner GS (2004) Mobilization of stem cells by granulocyte colony-stimulating factor for the regeneration of myocardial tissue after myocardial infarction. Dtsch Med Wochenschr 129(9):424–428PubMedGoogle Scholar