期刊
BASIC RESEARCH IN CARDIOLOGY
卷 114, 期 2, 页码 -出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00395-018-0713-y
关键词
Ischemia-reperfusion injury; Myocardial infarction; Sprouty1; Extracellular signal-regulated kinase; Glycogen synthase kinase-3
资金
- University of Oulu including Oulu University Hospital
- Academy of Finland [256908, 268505, 131020, 297094]
- Finnish Foundation for Cardiovascular Research
- Finnish Cultural Foundation
- Aarne Koskelo Foundation
- Emil Aaltonen Foundation
- Orion Research Foundation
- Sigrid Juselius Foundation
- Jane and Aatos Erkko Foundation
- Academy of Finland (AKA) [256908, 131020, 297094, 256908, 268505, 131020, 268505] Funding Source: Academy of Finland (AKA)
Sprouty1 (Spry1) is a negative modulator of receptor tyrosine kinase signaling, but its role in cardiomyocyte survival has not been elucidated. The aim of this study was to investigate the potential role of cardiomyocyte Spry1 in cardiac ischemia-reperfusion (I/R) injury. Infarct areas of mouse hearts showed an increase in Spry1 protein expression, which localized to cardiomyocytes. To investigate if cardiomyocyte Spry1 regulates I/R injury, 8-week-old inducible cardiomyocyte Spry1 knockout (Spry1 cKO) mice and control mice were subjected to cardiac I/R injury. Spry1 cKO mice showed reduction in release of cardiac troponin I and reduced infarct size after I/R injury compared to control mice. Similar to Spry1 knockdown in cardiomyocytes in vivo, RNAi-mediated Spry1 silencing in isolated cardiomyocytes improved cardiomyocyte survival following simulated ischemia injury. Mechanistically, Spry1 knockdown induced cardiomyocyte extracellular signal-regulated kinase (ERK) phosphorylation in healthy hearts and isolated cardiomyocytes, and enhanced ERK phosphorylation after I/R injury. Spry1-deficient cardiomyocytes showed better preserved mitochondrial membrane potential following ischemic injury and an increase in levels of phosphorylated ERK and phosphorylated glycogen synthase kinase-3 (GSK-3) in mitochondria of hypoxic cardiomyocytes. Overexpression of constitutively active GSK-3 abrogated the protective effect of Spry1 knockdown. Moreover, pharmacological inhibition of GSK-3 protected wild-type cardiomyocytes from cell death, but did not further protect Spry1-silenced cardiomyocytes from hypoxia-induced injury. Cardiomyocyte Spry1 knockdown promotes ERK phosphorylation and offers protection from I/R injury. Our findings indicate that Spry1 is an important regulator of cardiomyocyte viability during ischemia-reperfusion injury.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据