scholarly journals CD38 Causes Autophagic Flux Inhibition and Cardiac Dysfunction Through a Transcriptional Inhibition Pathway Under Hypoxia/Ischemia Conditions

2020 ◽  
Vol 8 ◽  
Author(s):  
Xingyue Zhang ◽  
Lingfei Li ◽  
Qiong Zhang ◽  
Qinglin Wei ◽  
Jiezhi Lin ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Autophagic Flux ◽  
Transcriptional Inhibition ◽  
Hypoxia Ischemia

scholarly journals Follistatin-Like 1 Attenuates Ischemia/Reperfusion Injury in Cardiomyocytes via Regulation of Autophagy

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Weijun Yang ◽  
Qunjun Duan ◽  
Xian Zhu ◽  
Kaiyu Tao ◽  
Aiqiang Dong
Keyword(s):  
Cell Viability ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Annexin V ◽  
Protective Role ◽  
Autophagic Flux ◽  
Rat Cardiomyocytes ◽  
Hypoxia Ischemia ◽  
Myocardial Ischemia Reperfusion

Background. The cardioprotective effect of FSTL1 has been extensively studied in recent years, but its role in myocardial ischemia/reperfusion injury (IRI) is unclear. In this study, we investigated the effect of FSTL1 pretreatment on myocardial IRI as well as the possible involvement of autophagic pathways in its effects. Methods. The effects of FSTL1 on the viability and apoptosis of rat cardiomyocytes were investigated after exposure of cardiomyocytes to hypoxia/ischemia by using the CCK-8 assay and Annexin V/PI staining. Further, western blot analysis was used to detect the effects of FSTL1 pretreatment on autophagy-associated proteins, and confocal microscopy was used to observe autophagic flux. To confirm the role of autophagy, the cells were treated with the autophagy promoter rapamycin or the autophagy inhibitor 3-methyladenine, and cell viability and apoptosis during IRI were observed. These effects were also observed after treatment with rapamycin or 3-methyladenine followed by FSTL1 administration and IRI. Results. FSTL1 pretreatment significantly increased viability and reduced apoptosis in cardiomyocytes exposed to hypoxia/ischemia conditions. Further, FSTL1 pretreatment affected the levels of the autophagy-related proteins and enhanced autophagic flux during IRI. In addition, cell viability was enhanced and apoptosis was decreased by rapamycin treatment, while these effects were reversed by 3-MA treatment. However, when the myocardial cells were pretreated with rapamycin or 3-methyladenine, there was no significant change in their viability or apoptosis with FSTL1 treatment during IRI. Conclusions. FSTL1 plays a protective role in myocardial IRI by regulating autophagy.

scholarly journals Pressure Overload-Induced Cardiac Dysfunction in Aged Male Adiponectin Knockout Mice Is Associated With Autophagy Deficiency

Endocrinology ◽  
2015 ◽  
Vol 156 (7) ◽  
pp. 2667-2677 ◽  
Author(s):  
James Won Suk Jahng ◽  
Subat Turdi ◽  
Vera Kovacevic ◽  
Keith Dadson ◽  
Ren-Ke Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Western Blotting ◽  
Light Chain ◽  
Cardiac Dysfunction ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Autophagic Flux ◽  
Microtubule Associated Proteins ◽  
Cardiac Strain ◽  
Associated Proteins

Heart failure is a leading cause of death, especially in the elderly or obese and diabetic populations. Various remodeling events have been characterized, which collectively contribute to the progression of heart failure. Of particular interest, autophagy has recently emerged as an important determinant of cardiac remodeling and function. Here, we used aged, 13-month-old, male adiponectin knockout (Ad-KO) or wild-type (wt) mice subjected to aortic banding to induce pressure overload (PO). Cardiac strain analysis using speckle tracking echocardiography indicated significant dysfunction at an earlier stage in Ad-KO than wt. Analysis of autophagy by Western blotting for Light Chain 3 or microtubule-associated proteins 1B and Sequestosome 1 together with transmission electron microscopy of left ventricular tissue indicated a lack of PO-induced cardiac autophagy in Ad-KO compared with wt mice. Associated with this was mitochondrial degeneration and evidence of enhanced endoplasmic reticulum stress. Western blotting for Light Chain 3 or microtubule-associated proteins 1B, examination of flux using tandem fluoresent tagged-Light Chain 3, and analysis of lysosomal activity in H9c2 cardiac myoblasts treated with adiponectin indicated that adiponectin enhanced autophagy flux. In conclusion, adiponectin directly stimulates autophagic flux and the lack of autophagy in response to PO in aged mice lacking adiponectin may contribute to cellular events which exacerbate the development of cardiac dysfunction.

scholarly journals Alternative Mitophagy Protects the Heart Against Obesity-Associated Cardiomyopathy

2021 ◽  
Author(s):  
Mingming Tong ◽  
Toshiro Saito ◽  
Peiyong Zhai ◽  
Shin-ichi Oka ◽  
Wataru Mizushima ◽  
...  
Keyword(s):  
Quality Control ◽  
Transcriptional Activation ◽  
Cardiac Dysfunction ◽  
Systolic Dysfunction ◽  
Chronic Phase ◽  
Normal Diet ◽  
Autophagic Flux ◽  
Control Mechanisms ◽  
Mitochondrial Quality Control ◽  
Obesity Cardiomyopathy

Rationale: Obesity-associated cardiomyopathy characterized by hypertrophy and mitochondrial dysfunction. Mitochondrial quality control mechanisms, including mitophagy, are essential for the maintenance of cardiac function in obesity-associated cardiomyopathy. However, autophagic flux peaks at around 6 weeks of high fat diet (HFD) consumption and declines thereafter. Objective: We investigated whether mitophagy is activated during the chronic phase of cardiomyopathy associated with obesity (obesity cardiomyopathy) after general autophagy is downregulated and, if so, what the underlying mechanism and the functional significance are. Methods and Results: Mice were fed either a normal diet (ND) or a HFD (60 kcal % fat). Mitophagy, evaluated using Mito-Keima, was increased after 3 weeks of HFD consumption and continued to increase after conventional mechanisms of autophagy were inactivated, at least until 24 weeks. HFD consumption time-dependently up-regulated both Ser555-phosphorylated Ulk1 and Rab9 in the mitochondrial fraction. Mitochondria were sequestrated by Rab9-positive ring-like structures in cardiomyocytes isolated from mice after 20 weeks of HFD consumption, consistent with the activation of alternative mitophagy. Increases in mitophagy induced by HFD consumption for 20 weeks were abolished in cardiac-specific ulk1 knockout mouse hearts, in which both diastolic and systolic dysfunction were exacerbated. Rab9 S179A knock-in mice, in which alternative mitophagy is selectively suppressed, exhibited impaired mitophagy and more severe cardiac dysfunction than control mice following HFD consumption for 20 weeks. Overexpression of Rab9 in the heart increased mitophagy and protected against cardiac dysfunction during HFD consumption. HFD-induced activation of Rab9-dependent mitophagy was accompanied by upregulation of TFE3, which plays an essential role in transcriptional activation of mitophagy. Conclusions: Ulk1-Rab9-dependent alternative mitophagy is activated during the chronic phase of HFD consumption and serves as an essential mitochondrial quality control mechanism, thereby protecting the heart against obesity cardiomyopathy.

scholarly journals (+)-Usnic Acid Inhibits Migration of c-KIT Positive Cells in Human Colorectal Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Wei Wu ◽  
Bing Hou ◽  
Changli Tang ◽  
Fucheng Liu ◽  
Jie Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Usnic Acid ◽  
Autophagic Flux ◽  
Mtor Inhibition ◽  
Tumor Cell Migration ◽  
Transcriptional Inhibition ◽  
Autophagic Degradation ◽  
Treatment Concentration ◽  
Hct116 Cells

Inhibition of tumor cell migration is a treatment strategy for patients with colorectal cancer (CRC). SCF-dependent activation of c-KIT is responsible for migration of c-KIT positive [c-KIT(+)] cells of CRC. Drug resistance to Imatinib Mesylate (c-KIT inhibitor) has emerged. Inhibition of mTOR can induce autophagic degradation of c-KIT. (+)-usnic acid [(+)-UA], isolated from lichens, has two major functions including induction of proton shuttle and targeting inhibition of mTOR. To reduce hepatotoxicity, the treatment concentration of (+)-UA should be lower than 10μM. HCT116 cells and LS174 cells were employed to investigate the inhibiting effect of (+)-UA (<10μM) on SCF-mediated migration of c-KIT(+) CRC cells. HCT116 cells were employed to investigate the molecular mechanisms. The results indicated that firstly, 8μM (+)-UA decreased ATP content via uncoupling; secondly, 8μM (+)-UA induced mTOR inhibition, thereby mediated activation suppression of PKC-A, and induced the autophagy of the completed autophagic flux that resulted in the autophagic degradation and transcriptional inhibition of c-KIT and the increase in LDH release; ultimately, 8μM (+)-UA inhibited SCF-mediated migration of CRC c-KIT(+) cells. Taken together, 8μM could be determined as the effective concentration for (+)-UA to inhibit SCF-mediated migration of CRC c-KIT(+) cells.

Abstract 83: Autophagy Protects the Heart Against Pressure Overload Induced Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Akihiro Shirakabe ◽  
Yoshiyuki Ikeda ◽  
Toshiro Saito ◽  
Peiyong Zhai ◽  
Junichi Sadoshima
Keyword(s):  
Heart Failure ◽  
Cardiac Dysfunction ◽  
Sham Group ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Autophagic Flux ◽  
Multiple Time ◽  
Double Positive ◽  
Lung Weight ◽  
Multiple Time Points

Autophagy is an important mechanism for the degradation of cytosolic proteins and organelles. We investigated how autophagy is regulated in the heart in response to pressure overload (PO). Mice were subjected to transverse aortic constriction (TAC) at multiple time points between 1 hours and 30 days. Left ventricular (LV) weight/tibial length (TL) was significantly elevated at Day 5 (6.21 ± 0.10 vs 4.59 ± 0.10, p<0.05) and thereafter. Ejection fraction (EF) was maintained at Day 7 (82.1±3.4 vs 78.4±3.2%), but gradually decreased thereafter (at Day 30; 51.0±4.5, p<0.05). The level of LC3II was rapidly increased and peaked at 3 hour (2.4 fold , p<0.05), returned to normal by 24 hours, and then significantly decreased at Day 5 (-40.0%, p<0.05) and thereafter. Autophagic flux was evaluated with tandem fluorescent LC3. At 6 hours, both GFP/RFP double positive (yellow) dots and RFP dots were significantly increased in the TAC group compared to the sham group with or without chloroquine (CQ) (yellow 12±2 vs 4±0 CQ(-), 23±3 vs 9±1 CQ(+); RFP 13±2 vs 5±1 CQ(-), 19±1 vs 13±1 CQ(+)). On the other hand, both yellow and RFP dots were significantly decreased at Day7 and thereafter in the TAC group compared to the sham group with or without CQ. These data suggest that autophagic flux is activated transiently after TAC, but is inactivated after Day 5. To examine the functional significance of autophagy during PO, beclin1 heterozygous KO ( beclin1 -hetKO) mice, atg7 cardiac specific KO (Atg7-CKO) mice, and cardiac-specific U6-shRNA beclin1 (U6shRNA beclin1 ) mice were subjected to TAC. At Day 7 or 14, decreases in EF (60.7 ± 4.8%, 53.8 ± 2.1% and 46.7 ± 5.9%, p<0.05) and increases in lung weight/TL (8.43 ± 0.87, 11.04 ± 4.16 and 18.76 ± 3.77, p<0.05) were exacerbated in beclin1 -hetKO, atg7 -CKO and U6shRNA beclin1 mice compared to in control mice. These results suggest that PO inhibits autophagy after Day5, which coincides with the development of cardiac dysfunction. Since heart failure is exacerbated by further suppression of autophagy, autophagy during PO protects the heart from cardiac dysfunction.

scholarly journals Nrf2 Deficiency Exaggerates Doxorubicin-Induced Cardiotoxicity and Cardiac Dysfunction

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Siying Li ◽  
Wenjuan Wang ◽  
Ting Niu ◽  
Hui Wang ◽  
Bin Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Adverse Effects ◽  
Cardiac Dysfunction ◽  
Protein Aggregates ◽  
Autophagic Flux ◽  
Related Factor ◽  
Causative Role ◽  
Myocardial Oxidative Stress ◽  
Underlying Mechanisms

The anticancer therapy of doxorubicin (Dox) has been limited by its acute and chronic cardiotoxicity. In addition to a causative role of oxidative stress, autophagy appears to play an important role in the regulation of Dox-induced cardiotoxicity. However, the underlying mechanisms remain unclear. Accordingly, we explored a role of nuclear factor erythroid-2 related factor 2 (Nrf2) in Dox-induced cardiomyopathy with a focus on myocardial oxidative stress and autophagic activity. In wild type (WT) mice, a single intraperitoneal injection of 25 mg/kg Dox rapidly induced cardiomyocyte necrosis and cardiac dysfunction, which were associated with oxidative stress, impaired autophagy, and accumulated polyubiquitinated protein aggregates. However, these Dox-induced adverse effects were exaggerated in Nrf2 knockout (Nrf2−/−) mice. In cultured cardiomyocytes, overexpression of Nrf2 increased the steady levels of LC3-II, ameliorated Dox-induced impairment of autophagic flux and accumulation of ubiquitinated protein aggregates, and suppressed Dox-induced cytotoxicity, whereas knockdown of Nrf2 exerted opposite effects. Moreover, the exaggerated adverse effects in Dox-intoxicated Nrf2 depleted cardiomyocytes were dramatically attenuated by forced activation of autophagy via overexpression of autophagy related gene 5 (Atg5). Thus, these results suggest that Nrf2 is likely an endogenous suppressor of Dox-induced cardiotoxicity by controlling both oxidative stress and autophagy in the heart.

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