Ischemic myocardial inflammatory signaling in starvation versus hypoxia-derived extracellular vesicles: A comparative analysis

Sabra, Mohamed; Sabe, Sharif A.; Harris, Dwight D.; Xu, Cynthia M.; Broadwin, Mark; Bellam, Krishnah G.; Banerjee, Debolina; Abid, M. Ruhul; Sellke, Frank W.

doi:10.1016/j.xjon.2023.10.004

Cited by 2 publications

(2 citation statements)

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“…Oxidative stress plays a crucial role in cardiovascular disease, contributing to the exacerbation of vascular injury and the progression to heart failure in patients with myocardial ischemia [34][35][36][37]. We have previously demonstrated increased myocardial perfusion, reduced apoptosis, and decreased inflammation with HEVs in our swine model of chronic myocardial ischemia [31][32][33]. This study was designed to provide a more elaborate account of these encouraging findings and represents our first attempt to understand how the intramyocardial injection of HEVs modulates the response to oxidative stress.…”

Section: Discussionmentioning

confidence: 67%

“…Given both our prior success with standard, normoxic EVs and the potential benefits of HEVs, our lab set out to test HEVs with a validated large animal (porcine) model of chronic myocardial ischemia [25,26]. With this model, we have shown reductions in apoptosis and myocardial inflammation as well as improved myocardial perfusion using HEVs [31][32][33]. The goal of this study is to extend these insights through an improved understanding the of the molecular underpinnings of the findings previously derived from our model, with a particular emphasis on oxidative stress pathways.…”

Section: Introductionmentioning

confidence: 99%

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Intramyocardial Injection of Hypoxia-Conditioned Extracellular Vesicles Modulates Response to Oxidative Stress in the Chronically Ischemic Myocardium

Harris,

Sabe,

Broadwin

et al. 2024

Bioengineering

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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.

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