Abstract
Autophagy participates in the progression of many diseases, comprising ischemia/ reperfusion (I/R). It is reported that it is involved in the protective mechanism of ischemic postconditioning (IPostC). According to research, neuronal nitric oxide synthase (nNOS) is also involved in the condition of I/R and IPostC. However, the relationship between nNOS, autophagy and IPostC has not been previously investigated. We hypothesize that IPostC promotes autophagy activity against I/R injury partially through nNOS-mediated pathways. Mouse hearts were subjected to I/R injury through the ligation of the left anterior descending coronary artery. H9c2 cells were subjected to hypoxia/reoxygenation (H/R) in vitro. IPostC, compared with I/R, restored nNOS activity, increased the formation of autophagosome and restored the impaired autophagic flux, thus autophagic activity was raised markedly. IPostC increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and suppressed mammalian target of rapamycin (mTOR), but a selective nNOS inhibitor abolished those effects. Similar effects of IPostC were demonstrated in H9c2 cells in vitro. IPostC decreased infarct size and preserved most of the normal structure. The level of reactive oxygen species (ROS) and cell apoptosis were reduced by IPostC with improved cell viability and mitochondrial membrane potential. However, an autophagy inhibitor suppressed the protective effects. These results suggest that IPostC promoted autophagy against I/R injury at least partially via the activation of nNOS/AMPK/mTOR pathway.
Highlights
Ischemic heart disease has a high morbidity and mortality; it is the leading cause of death throughout the world [1]
In order to study whether neuronal nitric oxide synthase (nNOS) is affected by ischemic postconditioning (IPostC), the expression of nNOS was measured in myocardium
Compared with the control group, there was no significant change in the expression of total nNOS in the I/R group and IPostC group
Summary
Ischemic heart disease has a high morbidity and mortality; it is the leading cause of death throughout the world [1]. Rapid reperfusion of the ischemic myocardium is still the current standard treatment for myocardial infarction [2] It potentially causes additional injury in the early period, such as disturbances in ionic homeostasis, reactive oxygen species (ROS) over production, inflammatory responses, mitochondrial dysfunction and calcium overload. Autophagy is the process of phagocytosing and degrading autologous cytoplasmic proteins or organelles, thereby accomplishing the metabolic needs of the cells themselves and the renewal of some organelles [7] It is a key regulator of I/R injury and is believed to play important roles in the heart during I/R [8]. According to our previous research, nNOS is involved in the myocardial I/R injury and participates in the cardioprotection of IPostC by alleviating oxidative stress and calcium overload [17]. We hypothesize that IPostC promotes autophagic activity against reperfusion injury during early reperfusion, partially via the activation of nNOS related pathways
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