C1q tumor necrosis factor-related protein-3 protects mesenchymal stem cells against hypoxia- and serum deprivation-induced apoptosis through the phosphoinositide 3-kinase/Akt pathway

Hou,Meng; Liu,Jingjin; Liu,Fang; Liu,Kai; Yu,Bo

doi:10.3892/ijmm.2013.1550

C1q tumor necrosis factor-related protein-3 protects mesenchymal stem cells against hypoxia- and serum deprivation-induced apoptosis through the phosphoinositide 3-kinase/Akt pathway

Authors:
- Meng Hou
- Jingjin Liu
- Fang Liu
- Kai Liu
- Bo Yu
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Affiliations: The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Heilongjiang Province, P.R. China, Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, P.R. China
Published online on: November 7, 2013 https://doi.org/10.3892/ijmm.2013.1550
Pages: 97-104

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Abstract

Bone marrow (BM)-derived mesenchymal stem cells (MSCs) represent the leading candidate cell for tissue regeneration in the ischemic myocardium. However, the poor survival of stem cells transplanted into the ischemic myocardium presents a major obstacle in stem cell-based therapy. C1q tumor necrosis factor-related protein 3 (CTRP3) is a newly identified adipokine, similar to adiponectin, with beneficial effects on metabolic regulation. It has been shown to enhance the survival of cardiomyocytes during ischemia, while its expression is reduced following ischemia. In the present study, we examined the hypothesis that CTRP3 may enhance the survival of MSCs during exposure to hypoxia/serum deprivation (SD), and attempted to elucidate the underlying mechanisms. MSCs were obtained from rat bone marrow and cultured. Apoptosis was induced by hypoxia/SD for up to 24 h and the apoptotic rates were assessed by flow cytometry. MSC proliferation was measured using a Cell Counting kit-8 assay. The expression levels of Akt, Bcl-2, Bax, cytochrome c and cleaved caspase-3 were detected by western blot analysis. Mitochondrial membrane potential was examined using a membrane-permeable dye. CTRP3 significantly reduced hypoxia/SD-induced apoptosis in a concentration-dependent manner. The hypoxia/SD-induced decrease in the Bcl-2/Bax ratio and the mitochondrial membrane potential, and the increase in cytochrome c and caspase-3 levels were largely reversed by CTRP3. The anti-apoptotic effects of CTRP3 were blocked by inhibiting the activation of phosphoinositide 3-kinase (PI3K)/Akt signaling pathway with the PI3K inhibitor, LY294002. In conclusion, CTRP3 is a novel anti-apoptotic adipokine that protects MSCs from hypoxia/SD-induced apoptosis through the PI3K/Akt signaling pathway.

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1	Lopez AD, Mathers CD, Ezzati M, Jamison DT and Murray CJ: Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 367:1747–1757. 2006. View Article : Google Scholar
2	Orlic D, Kajstura J, Chimenti S, et al: Bone marrow cells regenerate infarcted myocardium. Nature. 410:701–705. 2001. View Article : Google Scholar : PubMed/NCBI
3	Stamm C, Westphal B, Kleine HD, et al: Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet. 361:45–46. 2003. View Article : Google Scholar : PubMed/NCBI
4	Wollert KC, Meyer GP, Lotz J, et al: Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet. 364:141–148. 2004. View Article : Google Scholar
5	Zhang M, Methot D, Poppa V, Fujio Y, Walsh K and Murry CE: Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies. J Mol Cell Cardiol. 33:907–921. 2001. View Article : Google Scholar : PubMed/NCBI
6	Geng YJ: Molecular mechanisms for cardiovascular stem cell apoptosis and growth in the hearts with atherosclerotic coronary disease and ischemic heart failure. Ann NY Acad Sci. 1010:687–697. 2003. View Article : Google Scholar : PubMed/NCBI
7	Chao W, Shen Y, Li L and Rosenzweig A: Importance of FADD signaling in serum deprivation- and hypoxia-induced cardiomyocyte apoptosis. J Biol Chem. 277:31639–31645. 2002. View Article : Google Scholar : PubMed/NCBI
8	Bonavita F, Stefanelli C, Giordano E, et al: H9c2 cardiac myoblasts undergo apoptosis in a model of ischemia consisting of serum deprivation and hypoxia: inhibition by PMA. FEBS Lett. 536:85–91. 2003. View Article : Google Scholar : PubMed/NCBI
9	Kishore U, Gaboriaud C, Waters P, et al: C1q and tumor necrosis factor superfamily: modularity and versatility. Trends Immunol. 25:551–561. 2004. View Article : Google Scholar : PubMed/NCBI
10	Wong GW, Wang J, Hug C, Tsao TS and Lodish HF: A family of Acrp30/adiponectin structural and functional paralogs. Proc Natl Acad Sci USA. 101:10302–10307. 2004. View Article : Google Scholar : PubMed/NCBI
11	Schaffler A, Ehling A, Neumann E, et al: Genomic organization, promoter, amino acid sequence, chromosomal localization, and expression of the human gene for CORS-26 (collagenous repeat-containing sequence of 26-kDa protein). Biochim Biophys Acta. 1630:123–129. 2003. View Article : Google Scholar
12	Weigert J, Neumeier M, Schaffler A, et al: The adiponectin paralog CORS-26 has anti-inflammatory properties and is produced by human monocytic cells. FEBS Lett. 579:5565–5570. 2005. View Article : Google Scholar : PubMed/NCBI
13	Compton SA and Cheatham B: CTRP-3: blocking a toll booth to obesity-related inflammation. Endocrinology. 151:5095–5097. 2010. View Article : Google Scholar : PubMed/NCBI
14	Kopp A, Bala M, Buechler C, et al: C1q/TNF-related protein-3 represents a novel and endogenous lipopolysaccharide antagonist of the adipose tissue. Endocrinology. 151:5267–5278. 2010. View Article : Google Scholar : PubMed/NCBI
15	Kopp A, Bala M, Weigert J, et al: Effects of the new adiponectin paralogous protein CTRP-3 and of LPS on cytokine release from monocytes of patients with type 2 diabetes mellitus. Cytokine. 49:51–57. 2010. View Article : Google Scholar : PubMed/NCBI
16	Hofmann C, Chen N, Obermeier F, et al: C1q/TNF-related protein-3 (CTRP-3) is secreted by visceral adipose tissue and exerts antiinflammatory and antifibrotic effects in primary human colonic fibroblasts. Inflamm Bowel Dis. 17:2462–2471. 2011. View Article : Google Scholar
17	Yi W, Sun Y, Yuan Y, et al: C1q/tumor necrosis factor-related protein-3, a newly identified adipokine, is a novel antiapoptotic, proangiogenic, and cardioprotective molecule in the ischemic mouse heart. Circulation. 125:3159–3169. 2012. View Article : Google Scholar
18	Pittenger MF, Mackay AM, Beck SC, et al: Multilineage potential of adult human mesenchymal stem cells. Science. 284:143–147. 1999. View Article : Google Scholar : PubMed/NCBI
19	Zhu W, Chen J, Cong X, Hu S and Chen X: Hypoxia and serum deprivation-induced apoptosis in mesenchymal stem cells. Stem Cells. 24:416–425. 2006. View Article : Google Scholar : PubMed/NCBI
20	Chen J, Baydoun AR, Xu R, et al: Lysophosphatidic acid protects mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis. Stem Cells. 26:135–145. 2008. View Article : Google Scholar : PubMed/NCBI
21	Mangi AA, Noiseux N, Kong D, et al: Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med. 9:1195–1201. 2003. View Article : Google Scholar : PubMed/NCBI
22	Hahn JY, Cho HJ, Kang HJ, et al: Pre-treatment of mesenchymal stem cells with a combination of growth factors enhances gap junction formation, cytoprotective effect on cardiomyocytes, and therapeutic efficacy for myocardial infarction. J Am Coll Cardiol. 51:933–943. 2008. View Article : Google Scholar
23	Lu G, Haider HK, Jiang S and Ashraf M: Sca-1⁺ stem cell survival and engraftment in the infarcted heart: dual role for preconditioning-induced connexin-43. Circulation. 119:2587–2596. 2009.
24	Orlic D, Kajstura J, Chimenti S, et al: Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA. 98:10344–10349. 2001. View Article : Google Scholar : PubMed/NCBI
25	Li Q, Wang L, Tan W, et al: Identification of C1qTNF-related protein 4 as a potential cytokine that stimulates the STAT3 and NF-κB pathways and promotes cell survival in human cancer cells. Cancer Lett. 308:203–214. 2011.PubMed/NCBI
26	Zhu P, Tan MJ, Huang RL, et al: Angiopoietin-like 4 protein elevates the prosurvival intracellular O₂(−):H₂O₂ ratio and confers anoikis resistance to tumors. Cancer Cell. 19:401–415. 2011. View Article : Google Scholar : PubMed/NCBI
27	Albrecht-Schgoer K, Schgoer W, Holfeld J, et al: The angiogenic factor secretoneurin induces coronary angiogenesis in a model of myocardial infarction by stimulation of vascular endothelial growth factor signaling in endothelial cells. Circulation. 126:2491–2501. 2012. View Article : Google Scholar
28	Kanwar JR, Kamalapuram SK and Kanwar RK: Survivin signaling in clinical oncology: a multifaceted dragon. Med Res Rev. 33:765–789. 2013. View Article : Google Scholar : PubMed/NCBI
29	Shortt J, Martin BP, Newbold A, et al: Combined inhibition of PI3K-related DNA damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas. Blood. 121:2964–2974. 2013. View Article : Google Scholar : PubMed/NCBI
30	Xu R, Chen J, Cong X, Hu S and Chen X: Lovastatin protects mesenchymal stem cells against hypoxia- and serum deprivation-induced apoptosis by activation of PI3K/Akt and ERK1/2. J Cell Biochem. 103:256–269. 2008. View Article : Google Scholar