Intramyocardial injection of hypoxia-conditioned extracellular vesicles modulates apoptotic signaling in chronically ischemic myocardium.
Intramyocardial injection of hypoxia-conditioned extracellular vesicles modulates apoptotic signaling in chronically ischemic myocardium.
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DOI：
10.1016/j.xjon.2023.05.013
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发表时间：
2023-09
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影响因子：
--
通讯作者：
Sellke, Frank W
中科院分区：
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作者：
Harris, Dwight D;Sabe, Sharif A;Sabra, Mohamed;Xu, Cynthia M;Malhotra, Akshay;Broadwin, Mark;Banerjee, Debolina;Abid, M Ruhul;Sellke, Frank W
非手术慢性冠状动脉疾病的治疗有限。以前，我们的实验室已经研究了细胞外囊泡（EV）治疗作为一种潜在的治疗慢性冠状动脉疾病的猪模型，并证明改善心脏功能与心肌内EV注射治疗的猪。在这里，我们试图通过使用缺氧条件下的EV（HEV）来研究EV的潜在心脏益处。本研究旨在探讨戊型肝炎病毒对猪慢性缺血心肌细胞凋亡的影响。对14头约克郡猪在左回旋支动脉上放置ameroid缩窄器。两周后，猪再次接受左胸廓切开术，注射生理盐水（对照，n = 7）或HEV（n = 7）。5周后，对猪实施安乐死以收集组织。末端脱氧核苷酸转移酶dUTP缺口末端标记用于定量细胞凋亡。免疫印迹用于蛋白质定量。末端脱氧核苷酸转移酶dUTP缺口末端标记染色显示，与对照组相比，HEV组的细胞凋亡减少（P = .049）。HEV组抗凋亡信号分子磷酸化BAD显著增加（P = 0.005），B细胞淋巴瘤2显著减少（P = 0.006），磷酸化B细胞淋巴瘤与B细胞淋巴瘤2的比率增加（P <0.001）。此外，戊型肝炎病毒组的促生存信号标志物水平升高，包括磷酸肌醇3-激酶、磷酸化细胞外信号调节激酶1/2、磷酸化叉头盒蛋白O 1和磷酸化蛋白激酶B与蛋白激酶B的比值（均P <0.05）。在慢性心肌缺血中，用HEV治疗导致总体凋亡减少，这可能是通过激活促存活和抗凋亡信号通路。
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. 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. 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). 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.