Intramyocardial Injection of Hypoxia-Conditioned Extracellular Vesicles Modulates Response to Oxidative Stress in the Chronically Ischemic Myocardium
Introduction: Patients with advanced coronary artery disease (CAD) who are not eligible for stenting or surgical bypass procedures have limited treatment options. Extracellular vesicles (EVs) have emerged as a potential therapeutic target for the treatment of advanced CAD. These EVs can be condition...
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MDPI AG
2024-01-01
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| Series: | Bioengineering |
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| Online Access: | https://www.mdpi.com/2306-5354/11/2/125 |
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| author | Dwight D. Harris Sharif A. Sabe Mark Broadwin Cynthia Xu Christopher Stone Meghamsh Kanuparthy Akshay Malhotra M. Ruhul Abid Frank W. Sellke |
| author_facet | Dwight D. Harris Sharif A. Sabe Mark Broadwin Cynthia Xu Christopher Stone Meghamsh Kanuparthy Akshay Malhotra M. Ruhul Abid Frank W. Sellke |
| author_sort | Dwight D. Harris |
| collection | DOAJ |
| description | Introduction: Patients with advanced coronary artery disease (CAD) who are not eligible for stenting or surgical bypass procedures have limited treatment options. Extracellular vesicles (EVs) have emerged as a potential therapeutic target for the treatment of advanced CAD. These EVs can be conditioned to modify their contents. In our previous research, we demonstrated increased perfusion, decreased inflammation, and reduced apoptosis with intramyocardial injection of hypoxia-conditioned EVs (HEVs). The goal of this study is to further understand the function of HEVs by examining their impact on oxidative stress using our clinically relevant and extensively validated swine model of chronic myocardial ischemia. Methods: Fourteen Yorkshire swine underwent a left thoracotomy for the placement of an ameroid constrictor on the left circumflex coronary artery to model chronic myocardial ischemia. After two weeks of recovery, the swine underwent a redo thoracotomy with injection of either HEVs (n = 7) or a saline control (CON, n = 7) into the ischemic myocardium. Five weeks after injection, the swine were subjected to terminal harvest. Protein expression was measured using immunoblotting. OxyBlot analysis and 3-nitrotyrosine staining were used to quantify total oxidative stress. Results: There was a significant increase in myocardial expression of the antioxidants SOD 2, GPX-1, HSF-1, UCP-2, catalase, and HO-1 (all <i>p</i> ≤ 0.05) in the HEV group when compared to control animals. The HEVs also exhibited a significant increase in pro-oxidant NADPH oxidase (NOX) 1, NOX 3, p47phox, and p67phox (all <i>p</i> ≤ 0.05). However, no change was observed in the expression of NFkB, KEAP 1, and PRDX1 (all <i>p</i> > 0.05) between the HEV and CON groups. There were no significant differences in total oxidative stress as determined by OxyBlot and 3-nitrotyrosine staining (<i>p</i> = 0.64, <i>p</i> = 0.32) between the groups. Conclusions: Administration of HEVs in ischemic myocardium induces a significant increase in pro- and antioxidant proteins without a net change in total oxidative stress. These findings suggest that HEV-induced changes in redox signaling pathways may play a role in increased perfusion, decreased inflammation, and reduced apoptosis in ischemic myocardium. Further studies are required to determine if HEVs alter the net oxidative stress in ischemic myocardium at an earlier time point of HEV administration. |
| first_indexed | 2024-03-07T22:41:13Z |
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| spelling | doaj.art-0145e267b4514c1f8be0ec6b692e164e2024-02-23T15:07:53ZengMDPI AGBioengineering2306-53542024-01-0111212510.3390/bioengineering11020125Intramyocardial Injection of Hypoxia-Conditioned Extracellular Vesicles Modulates Response to Oxidative Stress in the Chronically Ischemic MyocardiumDwight D. Harris0Sharif A. Sabe1Mark Broadwin2Cynthia Xu3Christopher Stone4Meghamsh Kanuparthy5Akshay Malhotra6M. Ruhul Abid7Frank W. Sellke8Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USADivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USADivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USADivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USADivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USADivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USADivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USADivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USADivision of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USAIntroduction: Patients with advanced coronary artery disease (CAD) who are not eligible for stenting or surgical bypass procedures have limited treatment options. Extracellular vesicles (EVs) have emerged as a potential therapeutic target for the treatment of advanced CAD. These EVs can be conditioned to modify their contents. In our previous research, we demonstrated increased perfusion, decreased inflammation, and reduced apoptosis with intramyocardial injection of hypoxia-conditioned EVs (HEVs). The goal of this study is to further understand the function of HEVs by examining their impact on oxidative stress using our clinically relevant and extensively validated swine model of chronic myocardial ischemia. Methods: Fourteen Yorkshire swine underwent a left thoracotomy for the placement of an ameroid constrictor on the left circumflex coronary artery to model chronic myocardial ischemia. After two weeks of recovery, the swine underwent a redo thoracotomy with injection of either HEVs (n = 7) or a saline control (CON, n = 7) into the ischemic myocardium. Five weeks after injection, the swine were subjected to terminal harvest. Protein expression was measured using immunoblotting. OxyBlot analysis and 3-nitrotyrosine staining were used to quantify total oxidative stress. Results: There was a significant increase in myocardial expression of the antioxidants SOD 2, GPX-1, HSF-1, UCP-2, catalase, and HO-1 (all <i>p</i> ≤ 0.05) in the HEV group when compared to control animals. The HEVs also exhibited a significant increase in pro-oxidant NADPH oxidase (NOX) 1, NOX 3, p47phox, and p67phox (all <i>p</i> ≤ 0.05). However, no change was observed in the expression of NFkB, KEAP 1, and PRDX1 (all <i>p</i> > 0.05) between the HEV and CON groups. There were no significant differences in total oxidative stress as determined by OxyBlot and 3-nitrotyrosine staining (<i>p</i> = 0.64, <i>p</i> = 0.32) between the groups. Conclusions: Administration of HEVs in ischemic myocardium induces a significant increase in pro- and antioxidant proteins without a net change in total oxidative stress. These findings suggest that HEV-induced changes in redox signaling pathways may play a role in increased perfusion, decreased inflammation, and reduced apoptosis in ischemic myocardium. Further studies are required to determine if HEVs alter the net oxidative stress in ischemic myocardium at an earlier time point of HEV administration.https://www.mdpi.com/2306-5354/11/2/125extracellular vesicleshypoxia-conditioned extracellular vesiclesswinechronic myocardial ischemiaoxidative stress |
| spellingShingle | Dwight D. Harris Sharif A. Sabe Mark Broadwin Cynthia Xu Christopher Stone Meghamsh Kanuparthy Akshay Malhotra M. Ruhul Abid Frank W. Sellke Intramyocardial Injection of Hypoxia-Conditioned Extracellular Vesicles Modulates Response to Oxidative Stress in the Chronically Ischemic Myocardium Bioengineering extracellular vesicles hypoxia-conditioned extracellular vesicles swine chronic myocardial ischemia oxidative stress |
| title | Intramyocardial Injection of Hypoxia-Conditioned Extracellular Vesicles Modulates Response to Oxidative Stress in the Chronically Ischemic Myocardium |
| title_full | Intramyocardial Injection of Hypoxia-Conditioned Extracellular Vesicles Modulates Response to Oxidative Stress in the Chronically Ischemic Myocardium |
| title_fullStr | Intramyocardial Injection of Hypoxia-Conditioned Extracellular Vesicles Modulates Response to Oxidative Stress in the Chronically Ischemic Myocardium |
| title_full_unstemmed | Intramyocardial Injection of Hypoxia-Conditioned Extracellular Vesicles Modulates Response to Oxidative Stress in the Chronically Ischemic Myocardium |
| title_short | Intramyocardial Injection of Hypoxia-Conditioned Extracellular Vesicles Modulates Response to Oxidative Stress in the Chronically Ischemic Myocardium |
| title_sort | intramyocardial injection of hypoxia conditioned extracellular vesicles modulates response to oxidative stress in the chronically ischemic myocardium |
| topic | extracellular vesicles hypoxia-conditioned extracellular vesicles swine chronic myocardial ischemia oxidative stress |
| url | https://www.mdpi.com/2306-5354/11/2/125 |
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