Author + information
- Hyelim Parka,b,
- Hyewon Parka,b,
- Hyoeun Kima,b,
- Seung-Hyun Leea,b,
- Shanyu Cuia,b,
- Hui-Nam Paka,b,
- Moon-Hyoung Leea,b and
- Boyoung Jounga,b
Background: Microvesicles (MVs) contain bioactive molecules critical to intracellular signaling and have cardioprotective effects in ischemia/reperfusion (IR) injury hearts. This study investigated the cardioprotective utility of human-derived MVs in mouse, rat, and rabbit IR injury hearts and studied the principal mechanism by determining the expression levels of connexin43 (Cx43).
Methods: MVs were isolated from hypoxia-preconditioned human MSCs. Mouse, rat, and rabbit IR injury models were treated with MV solution (0.4μg/μL) via leg vein. Dual optical mapping were performed on IR model hearts to analyze action potential duration. The intracellular calcium dynamic was measured in HL-1 cells, neonatal and adult rat cardiomyocytes treated with MVs after hypoxic injury. The impact of MV injection on the Wnt signaling pathway activation and Cx43 expression was analyzed by western blot. To identify valuable targets for heart defects, microarray were used to obtain miRNA expression profiles from control and IR MV.
Results: Detection of PKH26 staining in IR+MV hearts confirmed successful MV delivery. The MV treatment significantly improved electrical conduction, diminished infarct size (24±2 vs. 8±1%, p<0.001), and reduced arrhythmias in all three animal models. Ca2+ wave frequency and amplitude were increased in hypoxia/reoxygenation (HR) cells, but reduced in HR+MV cells. MV treatment prevented Ca2+ overloading typically induced by HR injury in mouse, rat and rabbit cardiomyocytes. In addition, IR injury reduced the level of Wnt1, β-catenin, and Cx43 expression. However, MV injection enhanced Wnt1, β-catenin, and Cx43 levels while downregulating GSK 3β (p<0.05). Mir-26a level was significantly increased in MVs derived from IR injury, which was rescued by suppressing GSK 3β expression and led to Cx43 expression via Wnt signaling.
Conclusions: MVs derivied from hypoxia preconditioned MSCs universally improved electrical conduction, diminished the infract size, and reduced the incidence of arrhythmias in three mammalian IR injury models via activation of the Wnt signaling pathway and upregulation of Cx43. These findings highlight a new therapeutic tool in case of IR injury.
Poster Hall, Hall C
Friday, March 17, 2017, 10:00 a.m.-10:45 a.m.
Session Title: Arrhythmias and Clinical EP: Basic 1
Abstract Category: 4. Arrhythmias and Clinical EP: Basic
Presentation Number: 1107-074
- 2017 American College of Cardiology Foundation