Intramyocardial injection of hypoxia-conditioned extracellular vesicles modulates apoptotic signaling in chronically ischemic myocardiumCentral MessagePerspective
Dwight D. Harris, MD,
Sharif A. Sabe, MD,
Mohamed Sabra, MD,
Cynthia M. Xu, MD,
Akshay Malhotra,
Mark Broadwin, MD,
Debolina Banerjee, MD,
M. Ruhul Abid, MD, PhD,
Frank W. Sellke, MD
Affiliations
Dwight D. Harris, MD
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI
Sharif A. Sabe, MD
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI
Mohamed Sabra, MD
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI
Cynthia M. Xu, MD
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI
Akshay Malhotra
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI
Mark Broadwin, MD
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI
Debolina Banerjee, MD
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI
M. Ruhul Abid, MD, PhD
Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI
Frank W. Sellke, MD
Address for reprints: Frank W. Sellke, MD, Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, 2 Dudley St, MOC 360, Providence, RI 02905.; Division 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.
