Overexpression of SerpinE2/protease nexin-1 Contribute to Pathological Cardiac Fibrosis via increasing Collagen Deposition

Li, Xuelian; Zhao, Dandan; Guo, Zhenfeng; Li, Tianshi; Qili, Muge; Xu, Bin; Qian, Ming; Liang, Haihai; Xiaoqiang, E; Gitau, Samuel Chege; Wang, Lu; Huangfu, Longtao; Wu, Qiuxia; Xu, Chaoqian; Shan, Hongli

doi:10.1038/srep37635

Cited by 49 publications

(46 citation statements)

References 42 publications

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“…In our results, aspirin repressed p-Erk1/2 expression and blocked the MAPK-Erk1/2 pathway. Our previous study showed that p-Erk1/2 can activate serpinE2 via the Erk-dependent transcription activator Elk1 in myocardial fibroblasts [10]. This current study showed that aspirin can inhibit the expression of serpinE2 by suppressing the MAPK-Erk1/2 signalling pathway.…”

Section: Discussionmentioning

confidence: 74%

“…In our previous study, we found that serpinE2 was up-regulated in pathological cardiac fibrosis. The overexpression of serpinE2 leads to the accumulation of extracellular matrix protein and contributes to cardiac fibrosis [10]. In myocardium taken from TAC mice, serpinE2 was increased by 1.36±0.12-fold compared with the sham control group ( p <0.01).…”

Section: Resultsmentioning

confidence: 99%

“…The total amounts of protein from the fibroblasts or myocardial tissue were resolved using 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to nitrocellulose membranes (Millipore, Bedford, MA) as described in detail previously [10]. Anti-β-catenin, anti-TGF-β1, anti-p-Erk1/2(Phospho-p44/42 Erk1/2), anti-T-Erk1/2(Total p44/42 Erk1/2), and anti-phospho-Akt (Ser473) were obtained from Cell Signaling (Danvers, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

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Aspirin Reduces Cardiac Interstitial Fibrosis by Inhibiting Erk1/2-Serpine2 and P-Akt Signalling Pathways

Wang²,

Qili

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cardiac interstitial fibrosis is an abnormality of various cardiovascular diseases, including myocardial infarction, hypertrophy, and atrial fibrillation, and it can ultimately lead to heart failure. However, there is a lack of practical therapeutic approaches to treat fibrosis and reverse the damage to the heart. The purpose of this study was to investigate the effect of long-term aspirin administration on pressure overload–induced cardiac fibrosis in mice and reveal the underlying mechanisms of aspirin treatment. Methods: C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with 10 mg·kg^-1·day^-1 of aspirin for 4 weeks. Masson staining and a collagen content assay were used to detect the effects of aspirin on cardiac fibrosis in vivo and in vitro. Western blot and qRT-PCR were applied to examine the impact of aspirin on extracellular signal-regulated kinases (Erks), p-Akt/β-catenin, SerpinE2, collagen I, and collagen III levels in the mice heart. Results: Aspirin significantly suppressed the expression of α-smooth muscle actin (α-SMA; 1.19±0.19-fold) and collagen I (0.95±0.09-fold) in TAC mice. Aspirin, at doses of 100 and 1000 µM, also significantly suppressed angiotensin II-induced α-SMA and collagen I in cultured CFs. The enhanced phosphorylation of Erk1/2 caused by TAC (p-Erk1, 1.49±0.19-fold; p-Erk2, 1.96±0.68-fold) was suppressed by aspirin (p-Erk1, 1.04±0.15-fold; p-Erk2, 0.87±0.06-fold). SerpinE2 levels were suppressed via the Erk1/2 signalling pathway following treatment with aspirin (1.36±0.12-fold for TAC; 1.06±0.07-fold for aspirin+TAC). The p-Akt and β-catenin levels were also significantly inhibited in vivo and in vitro. Conclusions: Our study reveals a novel mechanism by which aspirin alleviates pressure overload-induced cardiac interstitial fibrosis in TAC mice by suppressing the p-Erk1/2 and p-Akt/β-catenin signalling pathways.

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Section: Discussionmentioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Aspirin Reduces Cardiac Interstitial Fibrosis by Inhibiting Erk1/2-Serpine2 and P-Akt Signalling Pathways

Wang²,

Qili

et al. 2018

Cell Physiol Biochem

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“…mice: ER stress and mitochondrial oxidative stress regulate each other and form a vicious cycle, resulting in apoptosis [19]. To evaluate the effect of reduced ER stress on the cardiac mitochondrial function and oxidative stress, we measured mRNA levels of the genes involved in mitochondrial function: cytochrome c oxidase subunit 3 (COX3), cytochrome b (CYTB ), ATP synthase Fo subunit 6 (ATP6) and NADH dehydrogenase, subunit 1 (ND1).…”

Section: Ap Improves Mitochondrial Function and Reduces Oxidative Stmentioning

confidence: 99%

Inhibition of ER Stress by 2-Aminopurine Treatment Modulates Cardiomyopathy in a Murine Chronic Chagas Disease Model

Plakkal¹,

Lizardo²,

Wang³

et al. 2018

Preprint

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Trypanosoma cruzi infection results in debilitating cardiomyopathy, which is a major cause of mortality and morbidity in the endemic regions of Chagas disease (CD). The pathogenesis of Chagasic cardiomyopathy (CCM) has been intensely studied as a chronic inflammatory disease until recent observations reporting the role of cardio-metabolic dysfunctions. In particular, we demonstrated accumulation of lipid droplets and impaired cardiac lipid metabolism in the hearts of cardiomyopathic mice and patients, and their association with impaired mitochondrial functions and endoplasmic reticulum (ER) stress in CD mice. In the present study, we examined whether treating infected mice with an ER stress inhibitor can modify the pathogenesis of cardiomyopathy during chronic stages of infection. T. cruzi infected mice were treated with an ER stress inhibitor 2-Aminopurine (2AP) during the indeterminate stage and evaluated for cardiac pathophysiology during the subsequent chronic stage. Our study demonstrates that inhibition of ER stress improves cardiac pathology caused by T. cruzi infection by reducing ER stress and downstream signaling of phosphorylated eukaryotic initiation factor (P-elF2α) in the hearts of chronically infected mice. Importantly, cardiac ultrasound imaging showed amelioration of ventricular enlargement, suggesting that inhibition of ER stress may be a valuable strategy to combat the progression of cardiomyopathy in Chagas patients.

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“…It was worth noting that, some other new smad-dependent signaling pathways were discovered in recent years. Such as endoglin [ 52 , 53 ], fibulin-2 [ 54 ], serpine1 [ 55 ], serpineE2 [ 56 ]. Tseliou et al found that, in rodent models of acute myocardial infarction, cardiospheres (CSps) secreted soluble endoglin and attenuate remodeling by inhibiting TGF-β1/smad signaling [ 52 ].…”

Section: Introductionmentioning

confidence: 99%

Transforming growth factor β: A potential biomarker and therapeutic target of ventricular remodeling

Zou

Zhu

et al. 2017

Oncotarget

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Transforming growth factor β (TGF-β) is a multifunctional cytokine that is synthesized by many types of cells and regulates the cell cycle. Increasing evidence has led to TGF-β receiving increased and deserved attention in recent years because it may play a potentially novel and critical role in the development and progression of myocardial fibrosis and the subsequent progress of ventricular remodeling (VR). Numerous studies have highlighted a crucial role of TGF-β in VR and suggest potential therapeutic targets of the TGF-β signaling pathways for VR. Changes in TGF-β activity may elicit anti-VR activity and may serve as a novel therapeutic target for VR therapy. This review we discusses the smad-dependent signaling pathway, such as TGF-β/Smads, TGF-β/Sirtuins, TGF-β/BMP, TGF-β/miRNAs, TGF-β/MAPK, and Smad-independent signaling pathway of TGF-β, such as TGF-β/PI3K/Akt, TGF-β/Rho/ROCK,TGF-β/Wnt/β-catenin in the cardiac fibrosis and subsequent progression of VR. Furthermore, agonists and antagonists of TGF-β as potential therapeutic targets in VR are also described.

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Overexpression of SerpinE2/protease nexin-1 Contribute to Pathological Cardiac Fibrosis via increasing Collagen Deposition

Cited by 49 publications

References 42 publications

Aspirin Reduces Cardiac Interstitial Fibrosis by Inhibiting Erk1/2-Serpine2 and P-Akt Signalling Pathways

Aspirin Reduces Cardiac Interstitial Fibrosis by Inhibiting Erk1/2-Serpine2 and P-Akt Signalling Pathways

Inhibition of ER Stress by 2-Aminopurine Treatment Modulates Cardiomyopathy in a Murine Chronic Chagas Disease Model

Transforming growth factor β: A potential biomarker and therapeutic target of ventricular remodeling

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