scholarly journals Apelin-13 Regulates Angiotensin II-Induced Cx43 Downregulation and Autophagy via the AMPK/mTOR Signaling Pathway in HL-1 Cells

2020 ◽  
pp. 813-822
Author(s):  
Y CHEN ◽  
X QIAO ◽  
L ZHANG ◽  
X LI ◽  
Q LIU
Keyword(s):  
Atrial Fibrillation ◽  
Angiotensin Ii ◽  
Signaling Pathway ◽  
Connexin 43 ◽  
Mtor Signaling ◽  
Atrial Remodeling ◽  
Mtor Signaling Pathway ◽  
Cx43 Expression ◽  
Compound C ◽  
Cell Hypertrophy

Atrial fibrillation is associated with atrial remodeling, in which connexin 43 (Cx43) and cell hypertrophy play important roles. In this study, apelin-13, an aliphatic peptide, was used to explore the protective effects of the adenosine monophosphate-activated protein kinase (AMPK)/mTOR signaling pathway on Cx43 expression and autophagy, using murine atrial HL-1 cells. The expression of Cx43, AMPK, B-type natriuretic peptide (BNP) and pathway-related proteins was detected by Western blot analysis. Cellular fluorescence imaging was used to visualize Cx43 distribution and the cytoskeleton. Our results showed that the Cx43 expression was significantly decreased in HL-1 cells treated with angiotensin II but increased in cells additionally treated with apelin-13. Meanwhile, apelin-13 decreased BNP expression and increased AMPK expression. However, the expression of Cx43 and LC3 increased by apelin-13 was inhibited by treatment with compound C, an AMPK inhibitor. In addition, rapamycin, an mTOR inhibitor, promoted the development of autophagy, further inhibited the protective effect on Cx43 expression and increased cell hypertrophy. Thus, apelin-13 enhances Cx43 expression and autophagy via the AMPK/mTOR signaling pathway, and serving as a potential therapeutic target for atrial fibrillation.

Active vitamin D activates chondrocyte autophagy to reduce osteoarthritis via mediating the AMPK–mTOR signaling pathway

2020 ◽  
Vol 98 (3) ◽  
pp. 434-442 ◽  
Author(s):  
Chunyu Kong ◽  
Changlei Wang ◽  
Yuquan Shi ◽  
Lei Yan ◽  
Junhua Xu ◽  
...  
Keyword(s):  
Vitamin D ◽  
Signaling Pathway ◽  
Therapeutic Option ◽  
Serum Levels ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Ampk Signaling ◽  
Hydroxyvitamin D ◽  
Compound C ◽  
Safranin O

Osteoarthritis (OA) is a common joint degenerative disease. Vitamin D (VD) is essential for bone health. We hypothesized that active VD could be used as a therapeutic treatment for OA. Low serum levels of 25-hydroxyvitamin D [25(OH)D] have been found in patients with OA, and thus the serum level of VD could be diagnostic of OA. To test this, we established a mouse model of OA. The results from staining with hematoxylin–eosin and Safranin O – Fast Green indicated that active VD reduced the symptoms of OA in mice. The results from Western blotting indicated that treatment with VD increased the activity of the p-AMPK–AMPK signaling pathway and decreased the p-mTOR–mTOR pathway; it also increased the ratio of LC3II:LC3I antibodies and the protein expression levels of Beclin-1, but decreased the level of p62. Further, treatment with VD reduced the levels of tumor necrosis factor-α and interleukin-6 both in cartilage tissues and in chondrocytes. Administration of the AMPK inhibitor compound C and autophagy inhibitor 3-methyladenine (3-MA) reversed these changes following VD treatment. In addition, the results from transfection with mRFP-GFP-LC3 indicated that active VD led to autophagosome aggregation in OA chondrocytes. 3-MA inhibited cell autophagy and promoted inflammation in OA. This study provides evidence that active VD activate chondrocyte autophagy to reduce OA inflammation via activating the AMPK–mTOR signaling pathway. Treatment with active VD could be a novel therapeutic option for OA.

Glucocorticoid Suppresses Connexin 43 Expression by Inhibiting the Akt/mTOR Signaling Pathway in Osteoblasts

2016 ◽  
Vol 99 (1) ◽  
pp. 88-97 ◽  
Author(s):  
Chen Shen ◽  
Mi Ran Kim ◽  
Jeong Mi Noh ◽  
Su Jin Kim ◽  
Sun-O Ka ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Connexin 43 ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway

scholarly journals NOX2-Derived Hydrogen Peroxide Impedes the AMPK/Akt-mTOR Signaling Pathway in Parkinson's Disease in Vitro Models

2021 ◽  
Author(s):  
Ruijie Zhang ◽  
Nana Zhang ◽  
Xiaoqing Dong ◽  
Xin Chen ◽  
Jing Ma ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Hydrogen Peroxide ◽  
Parkinson's Disease ◽  
Signaling Pathway ◽  
Neuronal Apoptosis ◽  
Mtor Signaling ◽  
Regulatory Proteins ◽  
Mtor Signaling Pathway ◽  
Compound C

Abstract Oxidative stress is closely related to the pathogenesis of Parkinson's disease (PD), a typical neurodegenerative disease. NADPH oxidase 2 (NOX2) is involved in hydrogen peroxide (H2O2) generation. Recently, we have reported that H2O2 and PD toxins, including 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenylpyridin-1-ium (MPP+) and rotenone, induce neuronal apoptosis by inhibiting mTOR pathway. Here, we show that 6-OHDA, MPP+ or rotenone induced H2O2 generation by upregulation of NOX2 and its regulatory proteins (p22phox, p40phox, p47phox, p67phox, and Rac1), leading to apoptotic cell death in PC12 cells and primary neurons. Pretreatment with catalase, a H2O2-scavenging enzyme, significantly blocked PD toxins-evoked NOX2-derived H2O2, thereby hindering activation of AMPK, inhibition of Akt/mTOR, induction of apoptosis in neuronal cells. Similar events were also seen in the cells pretreated with Mito-TEMPO, a mitochondria-specific superoxide scavenger, implying a mitochondrial H2O2-dependent mechanism involved. Further research revealed that inhibiting NOX2 with apocynin or silencing NOX2 attenuated the effects of PD toxins on AMPK/Akt/mTOR and apoptosis in the cells. Of importance, ectopic expression of constitutively active Akt or dominant negative AMPKα, or inhibition of AMPK with compound C suppressed PD toxins-induced expression of NOX2 and its regulatory proteins, as well as consequential H2O2 and apoptosis in the cells. Taken together, these results indicate that certain PD toxins can impede the AMPK/Akt-mTOR signaling pathway leading to neuronal apoptosis by eliciting NOX2-derived H2O2. Our findings suggest that neuronal loss in PD may be prevented by regulating of NOX2, AMPK/Akt-mTOR signaling and/or administering antioxidants to ameliorate oxidative stress.

scholarly journals Immunoproteasome Subunit β5i Promotes Ang II (Angiotensin II)–Induced Atrial Fibrillation by Targeting ATRAP (Ang II Type I Receptor–Associated Protein) Degradation in Mice

Hypertension ◽  
2019 ◽  
Vol 73 (1) ◽  
pp. 92-101 ◽  
Author(s):  
Jing Li ◽  
Shuai Wang ◽  
Yun-Long Zhang ◽  
Jie Bai ◽  
Qiu-Yue Lin ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Angiotensin Ii ◽  
Connexin 43 ◽  
Transforming Growth Factor ◽  
Negative Regulator ◽  
Atrial Remodeling ◽  
Type I ◽  
Ang Ii ◽  
Adeno Associated Virus ◽  
Virus Serotype

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and increases the risk of stroke, heart failure, and death. Ang II (angiotensin II) triggers AF, mainly through stimulation of the AT1R (Ang II type I receptor). The immunoproteasome is a highly efficient proteolytic machine derived from the constitutive proteasome, but the role it plays in regulating AT1R activation and triggering AF remains unknown. Here, we show that among the catalytic subunits, β5i (PSMB8) expression, and chymotrypsin-like activity were the most significantly upregulated in atrial tissue of Ang II–infused mice or serum from patients with AF. β5i KO (β5i knockout) in mice markedly attenuated Ang II-induced AF incidence, atrial fibrosis, inflammatory response, and oxidative stress compared with WT (wild type) animals, but injection with recombinant adeno-associated virus serotype 9–β5i increased these effects. Moreover, we found that ATRAP (AT1R-associated protein) was a target of β5i. Overexpression of ATRAP significantly attenuated Ang II-induced atrial remodeling and AF in recombinant adeno-associated virus serotype 9–β5i-injected mice. Mechanistically, Ang II upregulated β5i expression to promote ATRAP degradation, which resulted in activation of AT1R-mediated NF-κB signaling, increased NADPH oxidase activity, increased TGF (transforming growth factor)-β1/Smad signaling, and altered the expression of Kir2.1 and CX43 (connexin 43) in the atria, thereby affecting atrial remodeling and AF. In summary, this study identifies β5i as a negative regulator of ATRAP stability that contributes to AT1R activation and to AF, highlighting that targeting β5i activity may represent a potential therapeutic approach for the treatment of hypertensive AF.

Erratum to: Glucocorticoid Suppresses Connexin 43 Expression by Inhibiting the Akt/mTOR Signaling Pathway in Osteoblasts

2016 ◽  
Vol 99 (1) ◽  
pp. 98-98
Author(s):  
Chen Shen ◽  
Mi Ran Kim ◽  
Jeong Mi Noh ◽  
Su Jin Kim ◽  
Sun-O Ka ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Connexin 43 ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway

Ligustilide inhibited Angiotensin II induced A7r5 cell autophagy via Akt/mTOR signaling pathway

2021 ◽  
pp. 174184
Author(s):  
Zhenhui Luo ◽  
Ao Zeng ◽  
Yuankun Chen ◽  
Shumiao He ◽  
Siqing He ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Signaling Pathway ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
A7r5 Cell

Emodin Ameliorate High Glucose-induced Podocyte Apoptosis via Regulating AMPK/mTOR- mediated Autophagy Signaling Pathway

2021 ◽  
Author(s):  
Hong Liu ◽  
Yanglin Hu ◽  
Ge Shi ◽  
Wenqiang Yang ◽  
Fei Xiong ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
High Glucose ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Therapeutic Option ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Trypan Blue Exclusion ◽  
Compound C

Abstract Background: Podocyte apoptosis and autophagy dysfunction have been considered to be one of the important causes of diabetic nephropathy (DN). Emodin has the function of regulating autophagy. The present study was performed to investigate the effect of emodin on high glucose (HG)-induced podocyte apoptosis and whether the potential anti-apoptotic mechanism of emodin is related to the induction of AMPK/mTOR-mediated autophagy in MPC5 cells in vitro.Methods: The viability and apoptosis of podocytes (MPC5 cells) were detected using CCK-8 assay, trypan blue exclusion assay and flow cytometry analysis, respectively. The expression levels of Cleaved caspase-3, autophagy maker LC3 I/II, and AMPK/mTOR signaling pathway-related proteins were evaluated with western blot analysis. The changes of morphology and RFP-LC3 fluorescence were observed under microscopy.Results: HG (20-160 mmol/L) dose-dependently induced cell apoptosis in MPC5 cells, whereas emodin (4 μmol/L) significantly ameliorated HG-induced cell apoptosis and caspase-3 cleavage. Emodin (4 μmol/L) significantly increased LC3-II levels and induced RFP-LC3-containing punctate structures in MPC5 cells. Furthermore, the protective effects of emodin were mimicked by rapamycin (100 nmol/L). Moreover, emodin increased the phosphorylation of AMPK and suppressed the phosphorylation of mTOR. The AMPK inhibitor compound C (10 μmol/L) abolished emodin-induced autophagy activation.Conclusion: Emodin ameliorated HG-induced apoptosis of MPC5 cells in vitro that involved induction of autophagy through the AMPK/mTOR signaling pathway, which might provide a potential therapeutic option for DN.

Metformin Inhibits Abdominal Aortic Aneurysm Formation through the Activation of the AMPK/mTOR Signaling Pathway

2021 ◽  
pp. 1-11
Author(s):  
Jiaan He ◽  
Nan Li ◽  
Yichuan Fan ◽  
Xingzhi Zhao ◽  
Chengwei Liu ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Signaling Pathway ◽  
Mtor Signaling ◽  
Protective Mechanism ◽  
Mtor Signaling Pathway ◽  
Sprague Dawley ◽  
Downstream Signaling ◽  
Compound C ◽  
Abdominal Aortic

Background and Objective: Epidemiological evidence suggests that the antidiabetic drug metformin (MET) can also inhibit abdominal aortic aneurysm (AAA) formation. However, the underlying protective mechanism remains unknown. It has been reported that phosphorylated AMP-activated protein kinase (AMPK) levels are significantly lower in AAA tissues than control aortic tissues. AMPK activation can inhibit the downstream signaling molecule called mechanistic target of rapamycin (mTOR), which has also been reported be upregulated in thoracic aneurysms. Thus, blocking mTOR signaling could attenuate AAA progression. MET is a known agonist of AMPK. Therefore, in this study, we investigated if MET could inhibit formation of AAA by activating the AMPK/mTOR signaling pathway. Materials and Methods: The AAA animal model was induced by intraluminal porcine pancreatic elastase (PPE) perfusion in male Sprague Dawley rats. The rats were treated with MET or compound C (C.C), which is an AMPK inhibitor. AAA formation was monitored by serial ultrasound. Aortas were collected 4 weeks after surgery and subjected to immunohistochemistry, Western blot, and transmission electron microscopy analyses. Results: MET treatment dramatically inhibited the formation of AAA 4 weeks after PPE perfusion. MET reduced the aortic diameter, downregulated both macrophage infiltration and matrix metalloproteinase expression, decreased neovascularization, and preserved the contractile phenotype of the aortic vascular smooth muscle cells. Furthermore, we detected an increase in autophagy after MET treatment. All of these effects were reversed by the AMPK inhibitor C.C. Conclusion: This study demonstrated that MET activates AMPK and suppresses AAA formation. Our study provides a novel mechanism for MET and suggests that MET could be potentially used as a therapeutic candidate for preventing AAA.

scholarly journals Neferine Enhances Autophagy to Alleviate Cytotoxicity and Apoptosis Induced by CSE in AEC-II through AMPK/mTOR Signaling Pathway

2020 ◽  
Author(s):  
Mengmeng Wang ◽  
Haiyang Yu ◽  
Yuqing Sun ◽  
Pengpeng Cheng ◽  
Qian Wang ◽  
...  
Keyword(s):  
Protective Effect ◽  
Signaling Pathway ◽  
Cell Model ◽  
Cell Damage ◽  
Case Fatality ◽  
Chronic Respiratory Disease ◽  
Mtor Signaling ◽  
Autophagic Flux ◽  
Mtor Signaling Pathway ◽  
Compound C

Abstract COPD is a clinical common chronic respiratory disease, its incidence case fatality rate is higher, there is currently no cure drugs and methods. In this study, in order to make clear its role in the development of autophagy in COPD, COPD cell model is established.To further explore whether regulating autophagy could have a protective effect to fight against CSE-induced cytotoxicity and apoptosis, we choose neferine as an autophagy inducer. Neferine activated cell autophagy in an vitro CSE-induced COPD cell model and gradually attenuated CSE-induced cell apoptosis. Furthermore, this process happens largely through the AMPK/mTOR signaling pathway. As a autophagic flux inhibitor, chloroquine abolished the prosurvival autophagy effect, and AMPK inhibitor Compound C blocked neferine-mediated autophagy and then neferine failed to protect COPD cell model from CSE-induced apoptosis. Overall,our findings suggested that neferine possibly has a potentially protective effect in cell damage mechanisms caused by CSE. It hints that neferine has the prospect of turning into a potential therapeutics to cure CSE-induced cytotoxicity and apoptosis and even COPD patients.

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