Trimetazidine protects against cardiac ischemia/reperfusion injury via effects on cardiac miRNA-21 expression, Akt and the Bcl-2/Bax pathway

Ma, Ning; Bai, Jingyun; Zhang, Weihua; Luo, Hong; Zhang, Xin; Liu, Donghai; Qiao, Chenhui

doi:10.3892/mmr.2016.5773

Cited by 53 publications

(38 citation statements)

References 28 publications

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“…Conversely, FoxO3a was significantly up-regulated when miR-155 inhibitor was transfected into HK2 cells subjected to H/R treatment, indicating that FoxO3a is a direct target of miR-155. Recently, miRNAs have emerged as important mediators of translational control and as regulators of a wide range of biological processes [17][18][19][20][21]. Over-expression of miRNAs is a common phenomenon that occurs in various diseases, and aberrantly expressed miRNAs often participate in the pathogenesis of specific diseases, including ischemic renal diseases.…”

Section: Mir-155 Directly Targets Foxo3a In Hk2 Cells During Hrimentioning

confidence: 99%

“…Numerous studies have shown that miRNAs are involved in a wide variety of biological processes, including cell proliferation, differentiation, metastasis, apoptosis and immune responses [16][17][18][19]; moreover, they also function as prognostic markers in the development and progression of ischemic renal diseases by targeting pertinent genes [20][21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

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MiR-155 is Involved in Renal Ischemia-Reperfusion Injury via Direct Targeting of FoxO3a and Regulating Renal Tubular Cell Pyroptosis

Huang²,

梁英³

et al. 2016

Cell Physiol Biochem

102

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Background/Aims: Ischemia/reperfusion injury (IRI) plays a crucial role in renal transplantation and can cause renal failure associated with pyroptosis, a pro-inflammatory-induced programmed cell death. Small endogenous non-coding RNAs have been shown to be involved in renal ischemia/reperfusion injury. This study was performed to investigate which miRNAs regulate pyroptosis in response to renal ischemia/reperfusion injury and determine the mechanism underlying this regulation. Methods: An in vivo rat model of renal IRI was established, and the serum and kidneys were harvested 24 h after reperfusion to assess renal function and histological changes. For the in vitro study, the cultured human renal proximal tubular cell line HK-2 was subjected to 24 h of hypoxia (5% CO₂, 1% O₂, and 94% N2) followed by 12 h of reoxygenation (5% CO₂, 21% O₂, and 74% N₂). The mRNA expression levels were analyzed by real-time PCR, and the protein expression levels were analyzed using Western blot, immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA). Bioinformatics analyses were applied to predict miR-155 targets, which were then confirmed by a luciferase reporter assay. Results: We found that the levels of pyroptosis-related proteins, including caspase-1, caspase-11, IL-1β and IL-18, were significantly increased after renal ischemia/reperfusion injury. Similarly, hypoxia-reoxygenation injury (HRI) also induced pyroptosis in HK2 cells. Furthermore, our study revealed that miR-155 expression was substantially increased in the renal tissues of IRI rats and in HRI HK2 cells. Up-regulation of miR-155 promoted HK2 cell pyroptosis in HRI; conversely, knockdown of miR-155 attenuated this process. To understand the signaling mechanisms underlying the pro-pyroptotic activity of miR-155, we found that exogenous expression of miR-155 up-regulated the expression of caspase-1 as well as the pro-inflammatory cytokines IL-1β and IL-18. Moreover, miR-155 directly repressed FoxO3a expression and its downstream protein apoptosis repressor with caspase recruitment domain (ARC). Conclusions: Our study proposes a new signaling pathway of miR-155/FoxO3a/ARC leading to renal pyroptosis under ischemia/reperfusion injury conditions.

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Section: Mir-155 Directly Targets Foxo3a In Hk2 Cells During Hrimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MiR-155 is Involved in Renal Ischemia-Reperfusion Injury via Direct Targeting of FoxO3a and Regulating Renal Tubular Cell Pyroptosis

Huang²,

梁英³

et al. 2016

Cell Physiol Biochem

102

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“…In fact previous studies suggested that protein kinase C and Akt are mainly responsible for GSK-3β phosphorylation in ischemic preconditioning-induced cardioprotection [21,26]. Along the same lines, several reports have associated the protective effect of TMZ against I/R injury with its ability to activate AKT, which represents a major pathway mediating cell survival [27,28,29]. …”

Section: Discussionmentioning

confidence: 98%

GSK3β and VDAC Involvement in ER Stress and Apoptosis Modulation during Orthotopic Liver Transplantation

Zaoualí

Panisello

Lopez

et al. 2017

IJMS

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Abstract:We investigated the involvement of glycogen synthase kinase-3β (GSK3β) and the voltage-dependent anion channel (VDAC) in livers subjected to cold ischemia-reperfusion injury (I/R) associated with orthotopic liver transplantation (OLT). Rat livers were preserved in University of Wisconsin (UW) and Institute Georges Lopez (IGL-1) solution, the latter enriched or not with trimetazidine, and then subjected to OLT. Transaminase (ALT) and HMGB1 protein levels, glutamate dehydrogenase (GLDH), and oxidative stress (MDA) were measured. The AKT protein kinase and its direct substrates, GSK3β and VDAC, as well as caspases 3, 9, and cytochrome C and reticulum endoplasmic stress-related proteins (GRP78, pPERK, ATF4, and CHOP), were determined by Western blot. IGL-1+TMZ significantly reduced liver injury. We also observed a significant phosphorylation of AKT, which in turn induced the phosphorylation and inhibition of GSK3β. In addition, TMZ protected the mitochondria since, in comparison with IGL-1 alone, we found reductions in VDAC phosphorylation, apoptosis, and GLDH release. All these results were correlated with decreased ER stress. Addition of TMZ to IGL-1 solution increased the tolerance of the liver graft to I/R injury through inhibition of GSK3β and VDAC, contributing to ER stress reduction and cell death prevention.

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“…Further, trimetazidine-induced cardioprotection against cardiac I/R injury was reversed by knockdown of miR-21 using anti-miR-21 plasmids. Thus, trimetazidine-induced cardioprotection against cardiac I/R might be mediated via miR-21, and PI3K/Akt and Bcl-2/Bax pathways [169]. Very recently, miR-21 was found to enhance the protective effect of loperamide, a drug used in diarrhea treatment, against hypoxia/reoxygenation injury in rat cardiomyocytes, associated with the reduction of ROS production and apoptosis, likely via regulating the A-kinase anchoring protein 8 (Akap8) and BRCA1-associated RING domain 1 (Bard1) expression [170].…”

Section: Role Of Mir-1 and Mir-21 In Cardioprotection Other Than Ischmentioning

confidence: 99%

“…isoflurane-induced up-regulation of miR-21 associated with ↓PDCD4 protected cardiomyocytes against H 2 O 2 injury [166] isoflurane protected mouse hearts exposed to I/R via miR-21 and Akt/NOS/mPTP [167] trimetazidine-induced ↑miR-21 accompanied by cardioprotection against I/R, ↑p-Akt and ↑Bcl-2/Bax in rats. Cardioprotection reversed by anti-miR-21 [169] miR-21 enhanced protective effect of loperamide against H/R injury in rat cardiomyocytes associated with ↓ROS and ↓apoptosis [170] Non-pharmacological miR-1 down-regulation of miR-1 by traditional Chinese medicine Tanshinone IIA led to cardioprotection via inhibition of I/R-induced p-38 MAPK in rats [173] phenolic compound paeonol exerts cardioprotection against epirubicin-induced heart injury via regulation of miR-1, PI3K/AKT/mTOR and NF-κB [176] miR-21 resveratrol-induced up-regulation of miR-21 associated with protection against I/R in rats [168] miR transfection and delivery miR-21 adenovirus miR-21 transfection decreased IS via targeting PDCD4/AP-1 [62] adenovirus miR-21 transfection improved LV remodeling & ↓apoptosis in cardiac I/R in rats [67] lentivirus miR-21 transfection induced cardioprotection against I/R in mice manifested by ↓IS, ↓fibrosis and ↓apoptosis [64] miR-21 transfection to human cardiomyocytes ↓apoptosis via JNK/p38-MAPK/caspase-3 [68] chemically synthesized exogenous miR-21 reduced IS in mice, miR-21-induced protection was abolished with miR-21 inhibitor co-treatment [165] nanoparticle delivery of miR-21 to cardiac macrophages post-MI promoted angiogenesis, reduced hypertrophy, fibrosis, and apoptosis in the remote myocardium [75] miR-21 pretreatment exerted cardioprotection against CVB3 infection via targeting MAP2K3/p38-MAPK in mice [172] Exosomal miR miR-21 depletion of exosomal miR-21 reduced protective effect of conditioned medium in H 2 O 2 -induced oxidative stress in cardiomyocytes, and in rat hearts exposed to AMI [69] ↑miR-21 in CPC-derived exosomes prevented apoptosis in H9c2 cells via ↓PDCD4 [70] Abbreviations: I/R: ischemia/reperfusion; H/R: hypoxia/reoxygenation; AMI/MI: (acute) myocardial infarction; PDCD4: programmed cell death protein 4; AP-1: activator protein 1 (downstream molecule of PDCD4); ROS: reactive oxygen species; IS: infarct size; LV: left ventricle; CPC: cardiac progenitor cell; AF: atrial fibrillation; IPC: ischemic preconditioning; IPostC: ischemic postconditioning; RIPC: remote ischemic preconditioning; RIPerC: remote ischemic preconditioning; CVB3: coxsackievirus B3.…”

Section: Type Of Intervention Mir Findings Referencementioning

confidence: 99%

Potential Clinical Implications of miR-1 and miR-21 in Heart Disease and Cardioprotection

Kura

Kaločayová

Devaux

et al. 2020

IJMS

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The interest in non-coding RNAs, which started more than a decade ago, has still not weakened. A wealth of experimental and clinical studies has suggested the potential of non-coding RNAs, especially the short-sized microRNAs (miRs), to be used as the new generation of therapeutic targets and biomarkers of cardiovascular disease, an ever-growing public health issue in the modern world. Among the hundreds of miRs characterized so far, microRNA-1 (miR-1) and microRNA-21 (miR-21) have received some attention and have been associated with cardiac injury and cardioprotection. In this review article, we summarize the current knowledge of the function of these two miRs in the heart, their association with cardiac injury, and their potential cardioprotective roles and biomarker value. While this field has already been extensively studied, much remains to be done before research findings can be translated into clinical application for patient’s benefit.

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Trimetazidine protects against cardiac ischemia/reperfusion injury via effects on cardiac miRNA-21 expression, Akt and the Bcl-2/Bax pathway

Cited by 53 publications

References 28 publications

MiR-155 is Involved in Renal Ischemia-Reperfusion Injury via Direct Targeting of FoxO3a and Regulating Renal Tubular Cell Pyroptosis

MiR-155 is Involved in Renal Ischemia-Reperfusion Injury via Direct Targeting of FoxO3a and Regulating Renal Tubular Cell Pyroptosis

GSK3β and VDAC Involvement in ER Stress and Apoptosis Modulation during Orthotopic Liver Transplantation

Potential Clinical Implications of miR-1 and miR-21 in Heart Disease and Cardioprotection

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