U0126 attenuates ischemia/reperfusion-induced apoptosis and autophagy in myocardium through MEK/ERK/EGR-1 pathway

Wang, Anxing; Zhang, Huijun; Liang, Zongsuo; Kai, Xu; Qiu, Weifeng; Yao, Tian; Guo, Hong; Jia, Junjing; Xing, Erke; Chen, Rufei; Xiang, Zongxing; Liu, Jia

doi:10.1016/j.ejphar.2016.06.038

Cited by 64 publications

(45 citation statements)

References 27 publications

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“…I/R induced myocardium apoptosis, which becomes a key factor in MIRI pathogenesis 12. Type II programmed cell death, namely autophagy, is by mechanism distinct from apoptosis 13. Reduced superoxide dismutase (SOD) and increased lactate dehydrogenase (LDH) and malondialdehyde (MDA) concentration appeared in line with autophagy 14.…”

Section: Introductionmentioning

confidence: 99%

“…12 Type II programmed cell death, namely autophagy, is by mechanism distinct from apoptosis. 13 Reduced superoxide dismutase (SOD) and increased lactate dehydrogenase (LDH) and malondialdehyde (MDA) concentration appeared in line with autophagy. 14 Recent studies emphasized the dynamic process of autophagy, that is autophagic flux in understanding the impairment caused by MIRI.…”

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confidence: 99%

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Knockdown of lncRNA AK139328 alleviates myocardial ischaemia/reperfusion injury in diabetic mice via modulating miR‐204‐3p and inhibiting autophagy

Dong

Fang

et al. 2018

J Cellular Molecular Medi

131

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This study was aimed at investigating the effects of lncRNA AK139328 on myocardial ischaemia/reperfusion injury (MIRI) in diabetic mice. Ischaemia/reperfusion (I/R) model was constructed in normal mice (NM) and diabetic mice (DM). Microarray analysis was utilized to identify lncRNA AK139328 overexpressed in DM after myocardial ischaemia/reperfusion (MI/R). RT‐qPCR assay was utilized to investigate the expressions of lncRNA AK139328 and miR‐204‐3p in cardiomyocyte and tissues. Left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular ejection fraction (LVEF) and fractioning shortening (FS) were obtained by transthoracic echocardiography. Haematoxylin‐eosin (HE) staining and Masson staining were utilized to detect the damage of myocardial tissues degradation of myocardial fibres and integrity of myocardial collagen fibres. Evans Blue/TTC staining was used to determine the myocardial infarct size. TUNEL staining was utilized to investigate cardiomyocyte apoptosis. The targeted relationship between lncRNA AK139328 and miR‐204‐3p was confirmed by dual‐luciferase reporter gene assay. MTT assay was used for analysis of cardiomyocyte proliferation. Western blot was utilized to investigate the expression of alpha smooth muscle actin (α‐SMA), Atg7, Atg5, LC3‐II/LC3‐I and p62 marking autophagy. Knockdown of lncRNA AK139328 relieved myocardial ischaemia/reperfusion injury in DM and inhibited cardiomyocyte autophagy as well as apoptosis of DM. LncRNA AK139328 modulated miR‐204‐3p directly. MiR‐204‐3p and knockdown of lncRNA AK139328 relieved hypoxia/reoxygenation injury via inhibiting cardiomyocyte autophagy. Silencing lncRNA AK139328 significantly increased miR‐204‐3p expression and inhibited cardiomyocyte autophagy, thereby attenuating MIRI in DM.

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Knockdown of lncRNA AK139328 alleviates myocardial ischaemia/reperfusion injury in diabetic mice via modulating miR‐204‐3p and inhibiting autophagy

Dong

Fang

et al. 2018

J Cellular Molecular Medi

131

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“…To determine the role of ERK1/2 activation in the progression of HN, we employed U0126, a specific inhibitor of ERK1/2 [32], via I. P. at 10mg/kg every other day in HN rats. As shown in Figure 3C-3D, rats with HN displayed a remarkable up-regulation of ERK1/2 phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

Pharmacologic targeting ERK1/2 attenuates the development and progression of hyperuricemic nephropathy in rats

Liu

Shi

et al. 2017

Oncotarget

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The pathogenesis of hyperuricemia-induced chronic kidney disease is largely unknown. In this study, we investigated whether extracellular signal–regulated kinases1/2 (ERK1/2) would contribute to the development of hyperuricemic nephropathy (HN). In a rat model of HN induced by feeding mixture of adenine and potassium oxonate, increased ERK1/2 phosphorylation and severe glomerular sclerosis and renal interstitial fibrosis were evident, in parallel with diminished levels of renal function and increased urine microalbumin excretion. Administration of U0126, which is a selective inhibitor of the ERK1/2 pathway, improved renal function, decreased urine microalbumin and inhibited activation of renal interstitial fibroblasts as well as accumulation of extracellular proteins. U0126 also inhibited hyperuricemia-induced expression of multiple profibrogenic cytokines/chemokines and infiltration of macrophages in the kidney. Furthermore, U0126 treatment suppressed xanthine oxidase, which mediates uric acid production. It also reduced expression of the urate anion exchanger 1, which promotes reabsorption of uric acid, and preserved expression of organic anion transporters 1 and 3, which accelerate uric acid excretion in the kidney of hyperuricemic rats. Finally, U0126 inhibited phosphorylation of Smad3, a key mediator in transforming growth factor (TGF-β) signaling. In cultured renal interstitial fibroblasts, inhibition of ERK1/2 activation by siRNA suppressed uric acid-induced activation of renal interstitial fibroblasts. Collectively, pharmacologic targeting of ERK1/2 can alleviate HN by suppressing TGF-β signaling, reducing inflammation responses, and inhibiting the molecular processes associated with elevation of blood uric acid levels in the body. Thus, ERK1/2 inhibition may be a potential approach for the prevention and treatment of hyperuricemic nephropathy.

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“…There is increasing evidence that oxidative stress, apoptosis, Ca 2+ overload, and autophagy is involved in this process [9, 10]. Autophagy is a major catabolic mechanism by which mammalian cells degrade and recycle macromolecules and organelles at the basal level under normal conditions, contributing to maintaining intracellular homeostasis by removing protein aggregates and damaged organelles.…”

Section: Introductionmentioning

confidence: 99%

XuefuZhuyu decoction protected cardiomyocytes against hypoxia/reoxygenation injury by inhibiting autophagy

Shi

Zhu

Zhang

et al. 2017

BMC Complement Altern Med

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BackgroundXuefuZhuyu decoction (XFZY) is a well-known traditional Chinese herbal medicine for the treatment of various cardiovascular diseases, such as unstable angina pectoris and myocardial ischemia-reperfusion injury. However, the mechanism by which XFZY contributes to the amelioration of cardiac injury remains unclear.MethodsH9C2 cells were cultured under the hypoxic condition for 10 h and reoxygenated for 2 h. In the presence of various concentrations of XFZY for 12 h, the cell viability was measured by MTT assay. The protective effect of XFZY in hypoxia/reoxygenation (H/R) cell model was confirmed by measuring the amount of LDH released into the extracellular fluid. Cell apoptosis was measured by western blotting. The autophagy level of H9C2 cells and the correlative pathway were determined by transmission electron microscopy, Cyto-ID® Autophagy Detection Kit, and western blotting.ResultsIn this study, we investigated the effects of XFZY on H/R induced cardiac injury. The results showed that treatment with XFZY significantly inhibited autophagy induced by H/R, with decreased formation of autophagosomes as well as the expression of LC3-II/LC3-I ratio and Beclin 1 after H/R. Importantly, inhibition of autophagy by XFZY resulted in enhanced cell viability and decreased apoptosis. XFZY also inhibited the activation of AMPK and upregulated the phosphorylation of mammalian target of Rapamycin (mTOR).ConclusionsThe cardioprotective effects of XFZY during H/R were mediated by inhibiting autophagy via regulating AMPK-mTOR signaling pathways.

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U0126 attenuates ischemia/reperfusion-induced apoptosis and autophagy in myocardium through MEK/ERK/EGR-1 pathway

Cited by 64 publications

References 27 publications

Knockdown of lncRNA AK139328 alleviates myocardial ischaemia/reperfusion injury in diabetic mice via modulating miR‐204‐3p and inhibiting autophagy

Knockdown of lncRNA AK139328 alleviates myocardial ischaemia/reperfusion injury in diabetic mice via modulating miR‐204‐3p and inhibiting autophagy

Pharmacologic targeting ERK1/2 attenuates the development and progression of hyperuricemic nephropathy in rats

XuefuZhuyu decoction protected cardiomyocytes against hypoxia/reoxygenation injury by inhibiting autophagy

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