LOX‐1 is the prime target for mesenchymal stem cell exosome mediated cardioprotective effects

Abstract

ObjectiveMyocardial infarction (MI) is the leading cause of mortality worldwide. Attempts have been made to exploit stem cells by implanting them in the damaged cardiac tissue in hopes of regenerating/repairing cardiac muscle, limiting infarct size and improving cardiac function. However, the results of studies with the use of stem cells have been inconsistent. Recent studies show that use of mesenchymal stem cell (MSC) exosomes may limit cardiac injury, and even reverse cardiac damage. We studied the effect of MSC exosome administration on the extent of cardiac injury and function in an ischemia model.MethodsIschemia was induced in 8–10 week old healthy male wild‐type mice by ligating the left coronary artery (LCA). Mice were pretreated with MSC exosomes or saline as control. At 7 days after LCA ligation, the animals were euthanized and hearts were isolated. Hearts were sectioned into infarct and remote non‐infarct areas and used for further studies.ResultsWe observed that the infarct size was smaller in the exosome‐treated mice than in the saline‐treated mice (9±1 % vs. 12±1 %, respectively, p<0.01) and cardiac contractile function (fractional shortening) was preserved (42±4 % vs. 28±2 %, p<0.01) at 1 week after LCA ligation. Left ventricular wall thickness was preserved in exosome treated mice hearts (0.65±0.06 mm vs 0.33±0.02 mm, p<0.02). White blood cell accumulation in and around the infarct area was also reduced in exosome‐treated mice hearts (346±15 cells/hpf vs. 750±85 cells/hpf in saline‐treated hearts, p<0.01). Further, we observed that LOX‐1 and cleaved caspase‐3 were overexpressed in infarct areas of saline‐treated mice hearts. MSC exosome treatment reduced expression of LOX‐1 and cleaved caspase‐3 in infarct areas of the LCA ligated mice hearts (p<0.01). Expression of NLRP3 and TLR4 was also reduced in MSC‐exosome treated hearts. Proteomic analysis of the infarct areas of saline‐ and exosome‐treated LCA ligated hearts revealed differentially expressed proteins. The infarct areas of exosome‐treated (vs. saline‐treated hearts) showed upregulation of 75 specific proteins and downregulation of 37 proteins. Comparison of biological processes in infarct areas of exosome‐treated (vs saline‐treated LCA ligated heart) showed enrichment of processes governing cell communication, anaerobic respiration, apoptotic cell death while showing depletion of processes governing cell death, cardiac muscle cell apoptotic processes, angiotensin activated signaling, and activation of certain kinase pathways. The results of proteomic studies were concordant with the limitation of infarct size and preservation of functional data in the exosome‐treated hearts.ConclusionsMSC exosomes exert their cardioprotective effects by downregulating expression of LOX‐1 and caspase‐3 in LCA‐ligated mice hearts. Presumably, LOX‐1 inhibition led to inhibition of inflammatory pathways leading to mitigation of ischemic tissue damage.Support or Funding InformationVA Merit Review (Grant‐in‐Aid from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development, Washington, DC)MSC exosomes exhibit cardioprotective function by inhibiting LOX‐1Figure 1