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Apoptosis. 2018 Aug;23(7-8):436-448. doi: 10.1007/s10495-018-1469-4.

Protective effects of circulating microvesicles derived from ischemic preconditioning on myocardial ischemia/reperfusion injury in rats by inhibiting endoplasmic reticulum stress.

Liu M1,2, Wang Y1,3, Zhu Q1, Zhao J1, Wang Y1, Shang M1, Liu M4,5,6, Wu Y1, Song J7, Liu Y8.

Author information

1
Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China.
2
Department of Personnel, Tianjin University of Traditional Chinese Medicine, Health Industrial Park, Tianjin, 301617, China.
3
Department of Pharmacy, Tianjin Medical University General Hospital, 154 Anshan Road, Tianjin, 300052, China.
4
Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, Temple University School of Medicine, Philadelphia, PA, 19140, USA.
5
Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19140, USA.
6
Philadelphia VA Medical Center, Philadelphia, PA, 19140, USA.
7
Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China. songjunqiu@tmu.edu.cn.
8
Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China. liuyanxia@tmu.edu.cn.

Abstract

Microvesicles (MVs) have been shown to be involved in pathophysiology of ischemic heart diseases. However, the underlying mechanisms are still unclear. Here we investigated the effects of MVs derived from ischemic preconditioning (IPC-MVs) on myocardial ischemic/reperfusion (I/R) injury in rats. Myocardial IPC model was elicited by three cycles of ischemia and reperfusion of the left anterior descending (LAD) coronary artery. IPC-MVs from the peripheral blood of the above animal model were isolated by ultracentrifugation and characterized by flow cytometry and transmission electron microscopy. IPC-MVs were administered intravenously (7 mg/kg) at 5 min before reperfusion procedure in I/R injury model which was induced by 30-min ischemia and 120-min reperfusion of LAD in rats. We found that total IPC-MVs and different phenotypes, including platelet-derived MVs (PMVs), endothelial cell-derived MVs (EMVs), leucocyte-derived MVs and erythrocyte-derived MVs (RMVs) were all isolated which were identified membrane vesicles (< 1 µm) with corresponding antibody positive. The numbers of PMVs, EMVs and RMVs were significantly increased in circulation of IPC treated rats respectively. Additionally, treatment with IPC-MVs significantly alleviated damage of myocardium, and restored cardiac function of I/R injury rats, as evidenced by increased heart rate, and decreased the elevation of ST-segment. The size of myocardial infarction, lactate dehydrogenase activity, and the number of apoptotic cardiomyocytes were also reduced significantly with IPC-MVs treatment, coincident with the above function amelioration. Moreover, IPC-MVs decreased the activity of caspase 3, and the expression of endoplasmic reticulum stress (ERS) markers, GRP78, CHOP and caspase 12 indicating the involvement of ERS-specific apoptosis in I/R injury, and cardioprotective effects of IPC-MVs. In summary, our study demonstrated a novel mechanism of IPC in which circulating IPC-MVs could protect hearts from I/R injury in rats through attenuation of ERS-induced apoptosis. These findings provide new insight into therapeutic potential of IPC-induced MVs in cardioprotection against I/R injury.

KEYWORDS:

Apoptosis; Cardioprotection; Endoplasmic reticulum stress; Microvesicles; Myocardial ischemia/reperfusion; Myocardial ischemic preconditioning

PMID:
29980896
DOI:
10.1007/s10495-018-1469-4

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