Abstract
Adiponectin is a small peptide secreted and a key component of the endocrine system and immune system. Although globular adiponectin protects myocardial ischemia/reperfusion-induced cardiomyocyte injury, the protective mechanisms remain largely unresolved. Using a neonatal rat ventricular myocyte hypoxia/reoxygenation model, we investigated the role of its potential mechanisms of necroptosis in globular adiponectin-mediated protection in hypoxia/reoxygenation-induced cardiomyocyte injury as compared to apoptosis. We found that globular adiponectin treatment attenuated cardiomyocyte injury as indicated by increased cell viability and reduced lactate dehydrogenase release following hypoxia/reoxygenation. Immunofluorescence staining and Western blotting demonstrated that both necroptosis and apoptosis were triggered by hypoxia/reoxygenation and diminished by globular adiponectin. Necrostatin-1 (RIP1-specific inhibitor) and Z-VAD-FMK (pan-caspase inhibitor) only mimicked the inhibition of necroptosis and apoptosis, respectively, by globular adiponectin in hypoxia/reoxygenation-treated cardiomyocytes. Globular adiponectin attenuated reactive oxygen species production, oxidative damage, and p38MAPK and NF-κB signaling, all important for necroptosis and apoptosis. Collectively, our study suggests that globular adiponectin inhibits hypoxia/reoxygenation-induced necroptosis and apoptosis in cardiomyocytes probably by reducing oxidative stress and interrupting p38MAPK signaling.
Highlights
Acute myocardial infarction is a worldwide public health problem [1, 2]
A more remarkable decrease was seen in cardiomyocytes 6, 12, 24, and 36 h following reoxygenation as compared to cardiomyocytes exposed to hypoxia alone
+ + (2 μg/ml) expression levels of RIP1 and RIP3, key signaling molecules for necroptosis, in cardiomyocytes, we evaluated whether treatment of cardiomyocytes with necrostatin-1, a specific inhibitor to RIP1, mimics globular domain of adiponectin (gAd)-mediated suppression of necroptosis in cardiomyocytes
Summary
Acute myocardial infarction is a worldwide public health problem [1, 2]. Reperfusion therapies remain effective treatments for acute myocardial infarction. Myocardial ischemia/reperfusion results in largely unavoidable injury in cardiomyocytes [3, 4]. Major causes for myocardial ischemia/reperfusion injury include calcium overload, excessive reactive oxygen species (ROS) production, and inflammatory factor release, all together leading to cardiomyocyte death and myocardial dysfunction [5,6,7,8,9]. Apoptosis and necroptosis have been thought to be crucial in myocardial ischemia/reperfusion injury by regulating various intracellular signaling pathways [10]. Molecular mechanisms responsible for myocardial ischemia/reperfusion injury are still unclear.
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