ERK 
plays a role in modulating autophagy; ERK activation appears to have divergent roles in autophagy in different cell types. ERK induces autophagy in neuronal cell death and cancer cells and ERK upregulates starvation-induced autophagy by down-regulating Akt/mTOR/S6K. Similarly Wang et al., 8 Adiponectin Modulates Cardiac Myocyte Autophagy doi: 10.1371/journal.pone.0068697.g006 doi: 10.1371/journal.pone.0068697.g007 proposed that a non-canonical MEK/ERK module regulates autophagy through an AMPK-MEK/ERK-TSC-mTOR signaling pathway. Here mTOR regulates autophagy induced by starvation and non-starvation stimuli that activate MEK/ERK, suggesting a possible universal mechanism in autophagy regulation through mTOR. Thus, in our study pathophysiological levels of H2O2 induces an autophagic phenotype that is also mediated by ERK activation in addition to an AMPK-mTOR signaling pathway. In colorectal cancer cells, APN promotes cell survival during glucose deprivation by AMPK and PPAR activation and IGF-1/PI3k/Akt/mTOR pathway inhibition. Consistent with our present findings, oxidative stress activates the ERK/MAPK pathway and the 15930314 AMPK pathway in cardiomyocytes. Both signaling pathways may inhibit mTOR, ultimately leading to the downstream formation of autophagosomes. Low dose, physiological H2O2 has no effect on AMPK phosphorylation and pretreatment with APN increased AMPK phosphorylation in cardiomyocytes. Conversely, higher concentrations of H2O2 increased AMPK phosphorylation and inhibited mTOR phosphorylation, thus increasing autophagy. Pretreatment of cardiomyocytes with APN decreased H2O2-induced AMPK phosphorylation. Although others have reported that APN causes AMPK activation in cultured rat cardiomyocytes, none of these studies involved H2O2. Activation of Akt can also lead to decreased AMPK activity; thus it is possible that APN mediates Akt phosphorylation and decreases AMPK with resultant mTOR activation and inhibition of autophagy. It is therefore conceivable that APN activates AMPK under some conditions, whilst inhibiting it under other conditions such as elevated oxidative stress. In our study, H2O2-induced autophagy occurred through a predominant AMPK/mTOR/ERK pathway, which was inhibited by APN. We did not observe changes in beclin-1 levels similar to other cell systems which showed beclin-1 independent induced autophagy. Thus beclin-1 is not directly involved in the signaling mechanism we propose here. Other potential protective actions of APN against autophagy have been proposed, such as angiogenesis where APN administration increases VEGF expression and induces vascularization. However the antioxidant potential of APN in directly suppressing ROS may be most important. APN inhibits platelet aggregation by attenuating oxidative and nitrosative stress by inhibiting inducible nitric oxide synthase and superoxide production in vivo. Furthermore, in an ischemia/reperfusion-injury porcine model, APN modulated ROS metabolite levels and increased antioxidant levels. In conclusion, 12419798 APN protects against oxidative-stress mediated autophagic-induced cardiac myocyte death by suppressing the autophagic machinery predominantly via an ERK-mTOR-AMPK signaling mediated pathway. Recently in an experimental model of chronic AngII stimulation, LVH, MedChemExpress Chebulinic acid fibrosis, and left ventricular diastolic dysfunction were modulated by a mitochondrial targeted antioxidant peptide, SS-31. Thus targeting mitochondrial ROS may be a therapeutic option in Ang-II, a