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Updated: May 12, 2026
Intramyocardial Cell Delivery: Observations in Murine Hearts
Published on: January 24, 2014
Intramyocardial Injection of Hypoxia-Conditioned Extracellular Vesicles Modulates Response to Oxidative Stress in the
Dwight D Harris1, Sharif A Sabe1, Mark Broadwin1
1Division of Cardiothoracic Surgery, Department of Surgery, Cardiovascular Research Center, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI 02903, USA.
Insights
Hypoxia-conditioned extracellular vesicles (HEVs) increase antioxidant and pro-oxidant proteins in ischemic heart tissue. Despite these changes, HEVs do not alter overall oxidative stress, suggesting a role in improving heart function.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Oxidative Stress Biology
Background:
- Advanced coronary artery disease (CAD) lacks effective treatments for non-stentable/bypassable patients.
- Extracellular vesicles (EVs), particularly hypoxia-conditioned EVs (HEVs), show therapeutic potential for CAD.
- Previous studies indicated HEVs improve perfusion, reduce inflammation, and decrease apoptosis in ischemic myocardium.
Purpose of the Study:
- To investigate the impact of HEVs on oxidative stress in a swine model of chronic myocardial ischemia.
- To elucidate the role of HEVs in redox signaling pathways within the ischemic heart.
Main Methods:
- A swine model of chronic myocardial ischemia was established using an ameroid constrictor.
- Hypoxia-conditioned EVs (HEVs) or saline control were injected into the ischemic myocardium.
- Protein expression of antioxidants and oxidative stress markers was quantified via immunoblotting, OxyBlot, and 3-nitrotyrosine staining.
Main Results:
- HEV administration significantly increased myocardial expression of key antioxidants (SOD2, GPX-1, HSF-1, UCP-2, catalase, HO-1) and pro-oxidants (NOX1, NOX3, p47phox, p67phox).
- No significant changes were observed in NFkB, KEAP1, or PRDX1 expression.
- Total oxidative stress, measured by OxyBlot and 3-nitrotyrosine staining, showed no significant difference between HEV and control groups.
Conclusions:
- HEVs induce significant increases in both pro-oxidant and antioxidant proteins in ischemic myocardium without altering the net oxidative stress.
- These redox signaling pathway alterations suggest a mechanism for HEV-mediated improvements in perfusion, inflammation, and apoptosis.
- Further research is needed to determine if HEVs affect net oxidative stress at earlier time points post-administration.
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 p ≤ 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 p ≤ 0.05). However, no change was observed in the expression of NFkB, KEAP 1, and PRDX1 (all p > 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 (p = 0.64, p = 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.
