Related Experiment Video
Updated: Jul 14, 2025
Percutaneous Contrast Echocardiography-guided Intramyocardial Injection and Cell Delivery in a Large Preclinical Model
Published on: January 21, 2018
Intramyocardial injection of hypoxia-conditioned extracellular vesicles modulates apoptotic signaling in chronically
Dwight D Harris1, Sharif A Sabe1, Mohamed Sabra1
1Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI.
Objective:
Limited treatments exist for nonoperative chronic coronary artery disease. Previously, our laboratory has investigated extracellular vesicle (EV) therapy as a potential treatment for chronic coronary artery disease using a swine model and demonstrated improved cardiac function in swine treated with intramyocardial EV injection. Here, we seek to investigate the potential cardiac benefits of EVs by using hypoxia-conditioned EVs (HEV). Specifically, this study aims to investigate the effect of HEV on apoptosis in chronically ischemic myocardium in swine.
Methods:
Fourteen Yorkshire swine underwent placement of an ameroid constrictor on the left circumflex artery. Two weeks later, swine underwent redo left thoracotomy with injection of either saline (control, n = 7) or HEVs (n = 7). After 5 weeks, swine were euthanized for tissue collection. Terminal deoxynucleotidyl transferase dUTP nick end labeling was used to quantify apoptosis. Immunoblotting was used for protein quantification.
Results:
Terminal deoxynucleotidyl transferase dUTP nick end labeling staining showed a decrease in apoptosis in the HEV group compared with the control (P = .049). The HEV group exhibited a significant increase in the anti-apoptotic signaling molecule phospho-BAD (P = .005), a significant decrease in B-cell lymphoma 2 (P = .006) and an increase in the phospho-B-cell lymphoma to B-cell lymphoma 2 ratio (P < .001). Furthermore, the HEV group exhibited increased levels of prosurvival signaling markers including phosphoinositide 3-kinase, phosphor-extracellular signal-regulated kinase 1/2, phospho-forkhead box protein O1, and phospho-protein kinase B to protein kinase B ratio (all P < .05).
Conclusions:
In chronic myocardial ischemia, treatment with HEV results in a decrease in overall apoptosis, possibly through the activation of both pro-survival and anti-apoptotic signaling pathways.
