miR-21-5p/203a-3p promote ox-LDL-induced endothelial cell senescence through down-regulation of mitochondrial fission protein Drp1

Zhang, Jie; Liu, Weiqi; Peng, Junwen; Ma, Qin; Peng, Jun; Luo, Xiu-Ju

doi:10.1016/j.mad.2017.03.009

Cited by 35 publications

(24 citation statements)

References 27 publications

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“…Altered expression of miR-21 was reported in diseases like CVD, inflammationinduced diseases, or oncological diseases, and it is also involved in immunological and developmental processes 31 . The measured increase of miR-21 in HL hamsters' tissues is consistent with Zhang et al data showing significantly up-regulated miR-21-5p in plasma and aorta from HFD-fed rats 32 . In mice, published data show that miR-21 modulates vascular remodeling by regulating TGF-β signaling, but its target genes involved in this process are not known 33 .…”

Section: Discussionsupporting

confidence: 90%

Regulation of microRNAs in high-fat diet induced hyperlipidemic hamsters

Barbalata

Zhang

Dulceanu

et al. 2020

Sci Rep

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Dyslipidemia is a documented risk factor for cardiovascular diseases and other metabolic disorders. Therefore, the analysis of hyperlipidemia (HL)-related miRNAs is a potential approach for achieving new prognostic markers in lipid-metabolism related diseases. We aimed to analyze specific distribution of miRNAs in different tissues from HL animals. Golden Syrian hamsters were fed either regular chow (NL) or high-fat diet (HL) for 12 weeks. Microarray miRNAs profiling was performed in liver, heart and small intestine and data analyzed by R-studio software. Functional enrichment bioinformatics analysis was performed using miRWalk and DAVID tools. We observed a dysregulation of miRNAs in HL tissues evidencing a discrete distribution in the heart-liver axis and three lipid metabolism-related miRNAs were identified: hsa-miR-223-3p, hsa-miR-21-5p, and hsa-miR-146a-5p. Expression levels of these miRNAs were increased in HL livers and hearts. Functional bioinformatics analysis showed involvement of these miRNAs in the regulation of biological processes altered in HL conditions such as lipid metabolic process, fat cell differentiation, regulation of smooth muscle cells and cardiac septum development. We identified a set of miRNAs dysregulated in different tissues of HFD-induced HL hamsters. These findings motivate further studies aiming to investigate novel molecular mechanisms of lipid metabolism and atherogenic HL.

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Section: Discussionsupporting

confidence: 90%

Regulation of microRNAs in high-fat diet induced hyperlipidemic hamsters

Barbalata

Zhang

Dulceanu

et al. 2020

Sci Rep

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“…This contradiction can be explained by the fact that ox-LDL can induce endothelial senescence [28], accompanied by increased NADPH oxidases and NADPH oxidase-derived ROS [29]. In HUVEC, endothelial senescence was caused by suppressed expression of Nrf2 at the transcriptional level [30], and this decreased expression was modulated by direct targeting of Nrf2 mRNA by several microRNAs (miRNAs) [31,32]. AS-IV demonstrates a broad range of anti-oxidative stress by activating the Nrf2 antioxidant pathway, thereby protecting cortical neurons against ischemia/reperfusion injury [33], inhibiting hepatic stellate cell activation [34], and protecting lipopolysaccharide-induced microglia [35].…”

Section: Discussionmentioning

confidence: 99%

Astragaloside IV Protects Against Oxidized Low-Density Lipoprotein (ox-LDL)-Induced Endothelial Cell Injury by Reducing Oxidative Stress and Inflammation

Zhu

Zhang

2019

Med Sci Monit

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Background Endothelial injury is the main mechanism of atherosclerosis, and is caused by oxidized low-density lipoprotein (ox-LDL). Astragaloside IV (AS-IV) is the primary active ingredient of the Chinese herb Huangqi, and exhibits antioxidant and anti-inflammatory properties in cardiovascular diseases. This study investigated the protective effect of AS-IV in human umbilical vein endothelial cells (HUVECs). Material/Methods HUVEC cells were induced with ox-LDL to establish an in vitro atherosclerosis model. Then HUVECs were pretreated for 1 h with AS-IV at different concentrations (10, 20, and 50 μM) and then exposed to ox-LDL (100 μg/mL) for 48 h. The cell viability, lactate dehydrogenase (LDH) release, apoptosis, migration, intracellular reactive oxygen species (ROS), and NADPH oxidase activity of HUVECs were measured. qRT-PCR was performed to measure the mRNA expressions of Nrf2, HO-1, TNFα, and IL-6. Enzyme-linked immunosorbent assay (ELISA) was performed to measure the supernatant contents of TNFα and IL-6. Results Exposure of HUVECs to ox-LDL reduced cell viability and migration, induced apoptosis, and increased intracellular ROS production and NADPH oxidase. Pretreatment with AS-IV (10, 20, and 50 μM) significantly enhanced the cell viability and migration, suppressed LDH release, apoptosis, ROS production, and NADPH oxidase in HUVECs, in a concentration-dependent manner. The AS-IV (50 μM) alone did not show significant differences from control. AS-IV increased mRNA expressions of Nrf2 and HO-1 and decreased mRNA expressions of TNFα and IL-6 in the ox-LDL-HUEVC cells. Furthermore, AS-IV reduced supernatant contents of TNFα and IL-6. Conclusions Astragaloside IV prevents ox-LDL-induced endothelial cell injury by reducing apoptosis, oxidative stress, and inflammatory response.

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“…Given Drp1-dependent mitophagy plays a protective role against mitochondrial dysfunction and heart failure, 44 Drp1 downregulation is correlated with endothelial cell senescence and cancers, 48,49 we believe that increasing the profusion factors Mfn2 expression, which overexpression does not impair cardiac mitochondrial function, represents a safe therapeutic strategy for directly correcting excessive mitochondrial fragmentation. Given Drp1-dependent mitophagy plays a protective role against mitochondrial dysfunction and heart failure, 44 Drp1 downregulation is correlated with endothelial cell senescence and cancers, 48,49 we believe that increasing the profusion factors Mfn2 expression, which overexpression does not impair cardiac mitochondrial function, represents a safe therapeutic strategy for directly correcting excessive mitochondrial fragmentation.…”

Section: Discussionmentioning

confidence: 98%

Mitochondrial fusion mediated by fusion promotion and fission inhibition directs adult mouse heart function toward a different direction

Qin

Liu

et al. 2019

The FASEB Journal

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Mitochondrial fusion and fission are essential for heart function. Abrogating mitochondrial dynamism leads to cardiomyopathy. Excessive mitochondrial fragmentation is involved in most heart diseases, thus enhancing mitochondrial fusion will be a potential therapeutic strategy. To understand the effects of promoting mitochondrial fusion in adult cardiac, we investigated mice hearts, and cultured murine embryonic fibroblasts (MEFs), in which mitofusin 2 (Mfn2) overexpressed or dynamin-related protein 1 (Drp1) was abrogated concomitantly forcing mitochondrial fusion. Parallel studies revealed that fission-defective Drp1 knockout hearts and MEFs evoked stronger mitochondrial enlargement, enhanced mitophagy with mitochondrial volume decrease and increased mitochondrial calcium uptake, superoxide production, and permeability transition pore opening, contributed to cardiomyocyte apoptosis and dilated cardiomyopathy. Mfn2 overexpression in the adult heart is comparable with the control except for slight mitochondrial enlargement and mitochondrial volume increase, but without mitophagy induction. Moreover, Mfn2 overexpression increases mitochondrial biogenesis and fusion could protect against mitochondrial fragmentation and Drp1 deletion evoking mitophagy in MEFs. Our findings indicate that mitochondrial fusion provoked by fusion promotion and fission inhibition direct the different fate of heart, Mfn2 upregulation other than Drp1 downregulation well maintains heart mitochondrial function is a more safe strategy for correcting excessive mitochondrial fragmentation in hearts. K E Y W O R D Sadult heart, cardiac function, mitochondrial dynamics, mitochondrial fitness, therapeutic target 664 | QIN et al

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miR-21-5p/203a-3p promote ox-LDL-induced endothelial cell senescence through down-regulation of mitochondrial fission protein Drp1

Cited by 35 publications

References 27 publications

Regulation of microRNAs in high-fat diet induced hyperlipidemic hamsters

Regulation of microRNAs in high-fat diet induced hyperlipidemic hamsters

Astragaloside IV Protects Against Oxidized Low-Density Lipoprotein (ox-LDL)-Induced Endothelial Cell Injury by Reducing Oxidative Stress and Inflammation

Mitochondrial fusion mediated by fusion promotion and fission inhibition directs adult mouse heart function toward a different direction

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