Adipose-derived stem cell-released osteoprotegerin protects cardiomyocytes from reactive oxygen species-induced cell death

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Authors: Jiyun Lee ; Seahyung Lee ; Chang Youn Lee ; Hyang-Hee Seo ; Sunhye Shin ; Jung-Won Choi ; Sang Woo Kim ; Jong-Chul Park ; Soyeon Lim ; Ki-Chul Hwang

MeSH: Adipose Tissue/cytology ; Adipose Tissue/secretion ; Animals ; Cell Death/drug effects ; Cell Line ; Cell Survival/drug effects ; Culture Media, Conditioned/chemistry ; Culture Media, Conditioned/pharmacology* ; Gene Expression ; Heart Ventricles/cytology ; Heart Ventricles/metabolism ; Humans ; Hydrogen Peroxide/antagonists & inhibitors ; Hydrogen Peroxide/pharmacology ; Male ; Myocardial Reperfusion Injury/metabolism ; Myocardial Reperfusion Injury/pathology ; Myocardial Reperfusion Injury/physiopathology ; Myocardial Reperfusion Injury/therapy* ; Myocardium/metabolism ; Myocardium/pathology ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/drug effects* ; Myocytes, Cardiac/metabolism ; Osteoprotegerin/genetics* ; Osteoprotegerin/pharmacology ; Osteoprotegerin/secretion ; Primary Cell Culture ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/antagonists & inhibitors* ; Reactive Oxygen Species/metabolism ; Stem Cell Transplantation ; Stem Cells/cytology ; Stem Cells/secretion*

Keywords: Cardiomyocyte survival ; Osteoprotegerin ; Oxidative stress ; Stem cell

Abstract: BACKGROUND: The paracrine effect is likely the major mechanism of the adipose-derived stem cell (ASC)-mediated cardioprotective effect. However, the exact composition and nature of ASC-released paracrine factors remain elusive. In the present study, we examined the effect of osteoprotegerin (OPG), a stem cell-released decoy receptor for death ligand, on the survival of cardiomyocytes exposed to oxidative stress.

METHODS: The production of OPG from ASCs under oxidative stress was determined by ELISA and immunohistochemistry. The effects of OPG and the OPG-containing conditioned media of ASCs on the survival of cardiomyocytes were determined using a cell viability assay.

RESULTS: Hydrogen peroxide (H2O2) significantly increased OPG production from ASCs in vitro, and OPG production from the ASCs transplanted into the ischemia-reperfusion-injured heart was also observed. OPG significantly attenuated cardiomyocyte death in vitro. OPG-containing conditioned media of ASCs also significantly protected cardiomyocytes. Delivery of siRNA specific to OPG significantly decreased the OPG production of ASCs, and also offset the protective effect of the conditioned media of ASCs.

CONCLUSIONS: Our study strongly suggests that OPG is one of the prosurvival factors released from ASCs that may contribute to the ASC-mediated cardioprotection and calls for further studies to elucidate detailed underlying mechanisms.