Activated Protein C Ameliorates Diabetic Cardiomyopathy via Modulating OTUB1/YB-1/MEF2B Axis

Zhong, Xiaodan; Wang, Tao; Xie, Yang; Wang, Mengwen; Zhang, Wenjun; Dai, Lei; Lai, Jinsheng; Nie, Xiang; He, Xingwei; Madhusudhan, Thati; Zeng, Hesong; Wang, Hongjie

doi:10.3389/fcvm.2021.758158

Cited by 10 publications

(9 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, we showed that the YB-1 acts as a transcriptional suppressor, which binds directly to the promoter region of another important cardiomyopathy-related transcriptional factor myocyte enhancer factor 2B and suppresses its expression. Hyperglycemia caused proteasome-dependent YB-1 protein degradation results in myocyte enhancer factor 2B overexpression, which contributes to the development and formation of DCM (43).…”

Section: Discussionmentioning

confidence: 99%

ERK/RSK-mediated phosphorylation of Y-box binding protein-1 aggravates diabetic cardiomyopathy by suppressing its interaction with deubiquitinase OTUB1

Zhong

Wang

Zhang

et al. 2022

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

ERK/RSK-mediated phosphorylation of Y-box binding protein-1 aggravates diabetic cardiomyopathy by suppressing its interaction with deubiquitinase OTUB1

Zhong

Wang

Zhang

et al. 2022

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

“…The DCM model was implemented by placing mice on a high-fat (D12492, Research Diet) diet for 4 weeks, followed by overnight fasting and intraperitoneal injection with a dose of streptozotocin (STZ) (50 mg/kg × 5 days) dissolved in pH 4.5 sodium citrate buffer. After one week, mice with blood glucose higher than 16.7 mmol/L were considered as having DM [ 23 ] and continuous high-fat feeding. Control mice were given a normal diet and treated with sodium citrate buffer and continuous normal diet feeding.…”

Section: Methodsmentioning

confidence: 99%

6-Gingerol Alleviates Ferroptosis and Inflammation of Diabetic Cardiomyopathy via the Nrf2/HO-1 Pathway

Zhu

et al. 2022

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Background. Diabetes mellitus (DM) can induce cardiomyocyte injury and lead to diabetic cardiomyopathy (DCM) which presently has no specific treatments and consequently increase risk of mortality. Objective. To characterize the therapeutic effect of 6-gingerol (6-G) on DCM and identify its potential mechanism. Methods. In vivo streptozotocin- (STZ-) induced DM model was established by using a high-fat diet and STZ, followed by low-dose (25 mg/kg) and high-dose (75 mg/kg) 6-G intervention. For an in vitro DCM model, H9c2 rat cardiomyoblast cells were stimulated with high glucose ( glucose = 33 mM) and palmitic acid (100 μM) and then treated with 6-G (100 μM). Histological and echocardiographic analyses were used to assess the effect of 6-G on cardiac structure and function in DCM. Western blotting, ELISA, and real-time qPCR were used to assess the expression of ferroptosis, inflammation, and the Nrf2/HO-1 pathway-related proteins and RNAs. Protein expression of collagen I and collagen III was assessed by immunohistochemistry, and kits were used to assay SOD, MDA, and iron levels. Results. The results showed that 6-G decreased cardiac injury in both mouse and cell models of DCM. The cardiomyocyte hypertrophy and interstitial fibrosis were attenuated by 6-G treatment in vivo and resulted in an improved heart function. 6-G inhibited the expression of ferroptosis-related protein FACL4 and the content of iron and enhanced the expression of anti-ferroptosis-related protein GPX4. In addition, 6-G also diminished the secretion of inflammatory cytokines, including IL-1β, IL-6, and TNF-α. 6-G treatment activated the Nrf2/HO-1 pathway, enhanced antioxidative stress capacity proved by increased activity of SOD, and decreased MDA production. Compared with in vivo, 6-G treatment of H9c2 cells treated with high glucose and palmitic acid could produce a similar effect. Conclusion. These findings suggest that 6-G could protect against DCM by the mechanism of ferroptosis inhibition and inflammation reduction via enhancing the Nrf2/HO-1 pathway.

show abstract

“…These indicate that APC activates the activity of ERK1/2 to suppress apoptosis in IMN, and the inhibition of ERK1/2 activity has an impact on the blocking effect of APC on apoptosis. Recent study has shown that APC can promote YB-1 translocating into the nucleus through ERK1/2 activation [18,27]. The results of WB showed that YB-1 had obvious entry into the nucleus in the APC-treated IMN cell model.…”

Section: Erk1/2 Ameliorates Imn By Promoting Yb-1 Entry Into the Nucl...mentioning

confidence: 89%

“…Recent studies have identified the anti-inflammatory effects of APC in vascular endothelial cells, and APC is involved in regulatory crosstalk of EPCR, ERK, and NF-κB, thereby disrupting TNF signaling [17]. Further, previous data suggest that APC through PAR1/EPCR signaling maintain YB-1 levels by preventing YB-1 ubiquitination through OTUB1 [18,27]. Here, adding APC to IMN cells can increase the phosphorylation of ERK1/2 and promote the translocation of YB-1 to the nucleus.…”

Section: Discussionmentioning

confidence: 99%

“…Under healthy conditions, YB-1 is mainly found in the cytoplasm and plays a key role in regulating various aspects of RNA biology, but under conditions of genotoxic stress, YB-1 translocates to the nucleus, where activation affects immune response, apoptosis and tumor growth [20]. Previous study has shown that YB-1 can target the MEF2B promoter region to inhibit its expression and improve diabetic cardiomyopathy [18]. The role of YB-1 in calcineurin inhibitor-induced nephropathy was able to increase glomerular fibrosis but reduce interstitial fibrosis in the kidney [22].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

APC ameliorates idiopathic membranous nephropathy by affecting podocyte apoptosis through the ERK1/2/YB-1/PLA2R1 axis

Shen

Liao

et al. 2023

Mol Cell Biochem

View full text Add to dashboard Cite

Idiopathic membranous nephropathy (IMN) belongs to an important pathogenic category of adult nephrotic syndrome. PLA2R1 exposure is critical for triggering the pathogenesis of PLA2R1-related IMN. However, the pathogenesis of IMN and the molecular mechanism of treatment remain to be further clarified. The expression changes of activated protein C (APC) and PLA2R1 in IMN patients were quantified by qPCR. A zymosan activated serum (ZAS)-induced IMN podocyte model was established in vitro. Podocyte apoptosis was detected via flow cytometry and caspase‑3 assay. The expression levels of APC, p-ERK1/2, ERK1/2, YB-1 and PLA2R1 were detected by western blotting. The regulation relationship between YB-1 and PLA2R1 was detected by dual fluorescent reporter system. In IMN patients, the expression level of PLA2R1 was increased, whereas the expression level of APC was decreased. When APC was added to podocytes in vitro, the phosphorylation of ERK1/2 was increased, which could promote the translocation of YB-1 to the nucleus that reduces the expression of PLA2R1 at the cellular transcriptional level, thereby inhibiting podocyte apoptosis. Our study is the first to report that APC can improve membranous nephropathy by affecting podocyte apoptosis through the ERK1/2/YB-1/PLA2R1 axis. This study will provide a new targeted therapy for IMN patients with high PLA2R1 expression.

show abstract

Activated Protein C Ameliorates Diabetic Cardiomyopathy via Modulating OTUB1/YB-1/MEF2B Axis

Cited by 10 publications

References 53 publications

ERK/RSK-mediated phosphorylation of Y-box binding protein-1 aggravates diabetic cardiomyopathy by suppressing its interaction with deubiquitinase OTUB1

ERK/RSK-mediated phosphorylation of Y-box binding protein-1 aggravates diabetic cardiomyopathy by suppressing its interaction with deubiquitinase OTUB1

6-Gingerol Alleviates Ferroptosis and Inflammation of Diabetic Cardiomyopathy via the Nrf2/HO-1 Pathway

APC ameliorates idiopathic membranous nephropathy by affecting podocyte apoptosis through the ERK1/2/YB-1/PLA2R1 axis

Contact Info

Product

Resources

About