Pigment Epithelium-Derived Factor Mediates Autophagy and Apoptosis in Myocardial Hypoxia/Reoxygenation Injury

Kuo, Hsuan-Fu; Liu, Po-Len; Chong, Inn‐Wen; Liu, Yu-Peng; Chen, Yung‐Hsiang; Ku, Po-Ming; Li, Chia-Yang; Chen, Hsiu-Hua; Chiang, Hui-Ching; Wang, Chiao-Lin; Chen, Huang-Jen; Chen, Yen-Chieh; Hsieh, Chong‐Chao

doi:10.1371/journal.pone.0156059

Cited by 23 publications

(24 citation statements)

References 31 publications

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“…Field-emission transmission electron microscopy (FE-TEM) was performed as described previously (Kuo et al, 2016). In brief, tissue samples were fixed with 2.5% glutaraldehyde for 2 hr at 4°C.…”

Section: Field-emission Transmission Electron Microscopymentioning

confidence: 99%

“…The cells were cultured as described previously (Kuo et al, 2016 atmosphere at 37°C, and the culture medium was replaced every 4 to 5 days. With no exceptions, the cells were used between Passages 3 and 9.…”

Section: Cell Culturementioning

confidence: 99%

“…The western blot analyses were performed as described previously (Kuo et al, 2016). The protein concentrations of cell or tissue lysates were measured using the Lowry assay.…”

Section: Western Blot Analysismentioning

confidence: 99%

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Mitochondrial protection by simvastatin against angiotensin II‐mediated heart failure

Hsieh

Hsu

et al. 2019

British J Pharmacology

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Background and PurposeMitochondrial dysfunction plays a role in the progression of cardiovascular diseases including heart failure. 3‐Hydroxy‐3‐methylglutaryl‐CoA reductase inhibitors (statins), which inhibit ROS synthesis, show cardioprotective effects in chronic heart failure. However, the beneficial role of statins in mitochondrial protection in heart failure remains unclear.Experimental ApproachRats were treated with angiotensin II (1.5 mg·kg−1·day−1) or co‐administered simvastatin (oral, 10 mg·kg−1) for 14 days; and then administration was stopped for the following 14 days. Cardiac structure/function was examined by wheat germ agglutinin staining and echocardiography. Mitochondrial morphology and the numbers of lipid droplets, lysosomes, autophagosomes, and mitophagosomes were determined by transmission electron microscopy. Human cardiomyocytes were stimulated, and intracellular ROS and mitochondrial membrane potential (ΔΨ m) changes were measured by flow cytometry and JC‐1 staining, respectively. Autophagy and mitophagy‐related and mitochondria‐regulated apoptotic proteins were identified by immunohistochemistry and western blotting.Key ResultsSimvastatin significantly reduced ROS production and attenuated the disruption of ΔΨ m. Simvastatin induced the accumulation of lipid droplets to provide energy for maintaining mitochondrial function, promoted autophagy and mitophagy, and inhibited mitochondria‐mediated apoptosis. These findings suggest that mitochondrial protection mediated by simvastatin plays a therapeutic role in heart failure prevention by modulating antioxidant status and promoting energy supplies for autophagy and mitophagy to inhibit mitochondrial damage and cardiomyocyte apoptosis.Conclusion and ImplicationsMitochondria play a key role in mediating heart failure progression. Simvastatin attenuated heart failure, induced by angiotensin II, via mitochondrial protection and might provide a new therapy to prevent heart failure.

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Section: Field-emission Transmission Electron Microscopymentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

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Mitochondrial protection by simvastatin against angiotensin II‐mediated heart failure

Hsieh

Hsu

et al. 2019

British J Pharmacology

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“…The construction of ahHMGB1 lentiviral vector and transduction of cells were performed as described previously [24]. The hHMGB1 cDNA (GenBank accession numberNM_002128.4) was amplified by PCR using the following primers: forward , reverse .…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-200c inhibits epithelial-mesenchymal transition, invasion, and migration of lung cancer by targeting HMGB1

Liu

Chang

et al. 2017

PLoS ONE

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MicroRNAs (miRs) play critical roles in cancer development, proliferation, epithelial-mesenchymal transition (EMT), invasion, and migration through regulating the expression of oncogenes and tumour suppressor genes. Previous studies have indicated that miR-200c acts as a tumour suppressor in various cancers by downregulating high-mobility group box 1 (HMGB1) and thereby suppressing EMT and metastasis. In addition, miR-200c was reported to be downregulated and correlated with poor outcomes in non-small cell lung cancer (NSCLC). However, its functional role in HMGB1 regulation in NSCLC is still unclear. This study aimed to clarify whether miR-200c acts as a tumour suppressor in NSCLC by downregulating HMGB1, which is associated with EMT, invasion, cytoskeleton rearrangement, and migration in vitro and in vivo. In order to demonstrate HMGB1 downregulation by miR-200c, the NSCLC cell line A549 was transfected with miR-200c mimic or inhibitor. The mimic significantly reduced HMGB1 expression and suppressed EMT, invasion, and migration, while the inhibitor generated the opposite effects. Additionally, using xenograft mouse models, we confirmed that HMGB1 overexpression increased tumour EMT. In summary, our results demonstrated that miR-200c could suppress EMT, invasion, and migration of NSCLC cells by downregulating HMGB1.

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“…Moreover, ROS was crucial in hypoxia-induced autophagy [26, 27]. Therefore, we further explored if ROS plays a role in CLOCK-induced cell autophagy and dysfunction in HUVECs.…”

Section: Resultsmentioning

confidence: 99%

CLOCK Promotes Endothelial Damage by Inducing Autophagy through Reactive Oxygen Species

Tang

Lin

Guo

et al. 2016

Oxidative Medicine and Cellular Longevity

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A number of recent studies have implicated that autophagy was activated by reactive oxygen species (ROS). Our previous report indicated that CLOCK increased the accumulation of ROS under hypoxic conditions. In this study, we investigated the mechanisms by which CLOCK mediated endothelial damage, focusing on the involvement of oxidative damage and autophagy. Overexpression of CLOCK in human umbilical vein endothelial cells (HUVECs) showed inhibition of cell proliferation and higher autophagosome with an increased expression of Beclin1 and LC3-I/II under hypoxic conditions. In contrast, CLOCK silencing reversed these effects. Interestingly, pretreatment with 3-methyladenine (3-MA) resulted in the attenuation of CLOCK-induced cell autophagy and but did not influence the production of intracellular reactive oxygen species (ROS). Furthermore, Tiron (4,5-dihydroxy-1,3-benzene disulfonic acid-disodium salt), a ROS scavenger, significantly attenuated CLOCK-induced cell autophagy. In addition, we found that overexpression of CLOCK had no significant effects on the production of ROS and expression of Beclin1 and LC3-I/II under normoxic conditions in HUVEC. In this present investigation, our results suggested a novel mechanism of action of CLOCK in HUVECs, opening up the possibility of targeting CLOCK for the treatment of vascular diseases.

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Pigment Epithelium-Derived Factor Mediates Autophagy and Apoptosis in Myocardial Hypoxia/Reoxygenation Injury

Cited by 23 publications

References 31 publications

Mitochondrial protection by simvastatin against angiotensin II‐mediated heart failure

Mitochondrial protection by simvastatin against angiotensin II‐mediated heart failure

MicroRNA-200c inhibits epithelial-mesenchymal transition, invasion, and migration of lung cancer by targeting HMGB1

CLOCK Promotes Endothelial Damage by Inducing Autophagy through Reactive Oxygen Species

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