Conditioned medium from adipose-derived stem cells attenuates ischemia/reperfusion-induced cardiac injury through the microRNA-221/222/PUMA/ETS-1 pathway
| Autor: | Shu-Rung Lin, Chiang-Wen Lee, Yu-Chen Chen, Chi-Ming Pu, I-Ta Lee, Jaw-Shiun Tsai, Tzu-Lin Lee, Shu-Wha Lin, Yuh-Lien Chen, Tsai-Chun Lai |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine p38 mitogen-activated protein kinases Myocardial Infarction Medicine (miscellaneous) Apoptosis Myocardial Reperfusion Injury Ischemia/reperfusion injury Proto-Oncogene Protein c-ets-1 Andrology Mice 03 medical and health sciences 0302 clinical medicine Reperfusion therapy Annexin Fibrosis Puma Animals Medicine Myocytes Cardiac p53 upregulated modulator of apoptosis ADSC-CM miR-221/222 Pharmacology Toxicology and Pharmaceutics (miscellaneous) Mice Knockout TUNEL assay Cell Death biology business.industry Myocardium Stem Cells Tumor Suppressor Proteins fibrosis Mesenchymal Stem Cells medicine.disease biology.organism_classification Mice Inbred C57BL MicroRNAs 030104 developmental biology Adipose Tissue Culture Media Conditioned Reperfusion Injury 030220 oncology & carcinogenesis Reperfusion biology.protein Apoptosis Regulatory Proteins business Research Paper |
| Zdroj: | Theranostics |
| ISSN: | 1838-7640 |
| DOI: | 10.7150/thno.52677 |
| Popis: | Rationale: Cardiovascular diseases, such as myocardial infarction (MI), are the leading causes of death worldwide. Reperfusion therapy is the common standard treatment for MI. However, myocardial ischemia/reperfusion (I/R) causes cardiomyocyte injury, including apoptosis and fibrosis. We aimed to investigate the effects of conditioned medium from adipose-derived stem cells (ADSC-CM) on apoptosis and fibrosis in I/R-treated hearts and hypoxia/reoxygenation (H/R)-treated cardiomyocytes and the underlying mechanisms. Methods: ADSC-CM was collected from ADSCs. The effects of intramuscular injection of ADSC-CM on cardiac function, cardiac apoptosis, and fibrosis examined by echocardiography, Evans blue/TTC staining, TUNEL assay, and Masson's trichrome staining in I/R-treated mice. We also examined the effects of ADSC-CM on apoptosis and fibrosis in H/R-treated H9c2 cells by annexin V/PI flow cytometry, TUNEL assay, and immunocytochemistry. Results: ADSC-CM treatment significantly reduced heart damage and fibrosis of I/R-treated mice and H/R-treated cardiomyocytes. In addition, the expression of apoptosis-related proteins, such as p53 upregulated modulator of apoptosis (PUMA), p-p53 and B-cell lymphoma 2 (BCL2), as well as the fibrosis-related proteins ETS-1, fibronectin and collagen 3, were significantly reduced by ADSC-CM treatment. Moreover, we demonstrated that ADSC-CM contains a large amount of miR-221/222, which can target and regulate PUMA or ETS-1 protein levels. Furthermore, the knockdown of PUMA and ETS-1 decreased the induction of apoptosis and fibrosis, respectively. MiR-221/222 overexpression achieved similar results. We also observed that cardiac I/R markedly increased apoptosis and fibrosis in miR-221/222 knockout (KO) mice, while ADSC-CM decreased these effects. The increased phosphorylation of p38 and NF‐κB not only mediated myocardial apoptosis through the PUMA/p53/BCL2 pathway but also regulated fibrosis through the ETS-1/fibronectin/collagen 3 pathway. Conclusions: Overall, our results show that ADSC-CM attenuates cardiac apoptosis and fibrosis by reducing PUMA and ETS-1 expression, respectively. The protective effect is mediated via the miR-221/222/p38/NF-κB pathway. |
| Databáze: | OpenAIRE |
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