title: Ischemia/Reperfusion injury protection by mesenchymal stem cell derived antioxidant capacity.
abstract: Mesenchymal stem cell (MSC) transplantation after ischemia/reperfusion (I/R) injury reduces infarct size and improves cardiac function. We used mouse ventricular myocytes (VMs) in an in vitro model of I/R to determine the mechanism by which MSCs prevent reperfusion injury by paracrine signaling. Exposure of mouse VMs to an ischemic challenge depolarized their mitochondrial membrane potential (Ψmito), increased their diastolic Ca(2+), and significantly attenuated cell shortening. Reperfusion of VMs with Ctrl tyrode or MSC-conditioned tyrode (ConT) resulted in a transient increase of the Ca(2+) transient amplitudes in all cells. ConT-reperfused cells exhibited a decreased number early after depolarization (EADs) (ConT: 6.3% vs. Ctrl: 28.4%) and prolonged survival (ConT: 58% vs. Ctrl: 33%). Ψmito rapidly recovered in Ctrl as well as ConT-treated VMs on reperfusion; however, in Ctrl solution, an exaggerated hyperpolarization of Ψmito was determined that preceded the collapse of Ψmito. The ability of ConT to attenuate the hyperpolarization of Ψmito was suppressed on inhibition of the PI3K/Akt signaling pathway or IK,ATP. However, protection of Ψmito was best mimicked by the reactive oxygen species (ROS) scavenger mitoTEMPO. Analysis of ConT revealed a significant antioxidant capacity that was linked to the presence of extracellular superoxide dismutase (SOD3) in ConT. In conclusion, MSC ConT protects VMs from simulated I/R injury by its SOD3-mediated antioxidant capacity and by delaying the recovery of Ψmito through Akt-mediated opening of IK,ATP. These changes attenuate reperfusion-induced ROS production and prevent the opening of the permeability transition pore and arrhythmic Ca(2+) release.
authors.affiliation: Section of Cardiology, Department of Medicine, Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois 60612-7323, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: DeSantiago
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Bare
authors.forename: Kathrin
authors.initials: K
authors.lastname: Banach
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D048429:Cell Size; D002470:Cell Survival; D002478:Cells, Cultured; D007552:Isotonic Solutions / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010880:Piperidines / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D007552:Isotonic Solutions; C555916:MitoTEMPO; D009943:Organophosphorus Compounds; D010880:Piperidines; D017382:Reactive Oxygen Species; C037692:Tyrode's solution; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; D002118:Calcium