scholarly journals Lcz696 Alleviates Myocardial Fibrosis After Myocardial Infarction Through the sFRP-1/Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Liu ◽  
Xuehui Zheng ◽  
Chen Zhang ◽  
Chunmei Zhang ◽  
Peili Bu
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Signaling Pathway ◽  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Corn Oil ◽  
Inhibitory Effect ◽  
Neprilysin Inhibitor ◽  
Angiotensin Receptor Neprilysin Inhibitor ◽  
Related Proteins

Background: Lcz696 (ARNI, angiotensin receptor–neprilysin inhibitor; sacubitril/valsartan) shows an inhibitory effect on fibrosis after myocardial infarction (MI). However, the underlying signaling mechanisms are poorly understood. The Wnt/β-catenin signaling pathway is activated after MI and participates in the process of myocardial fibrosis. Here, we aimed to assess the efficacy of ARNI for alleviating myocardial fibrosis after MI and hypothesized that ARNI alleviates myocardial fibrosis by inhibiting the Wnt/β-catenin signaling pathway and overexpressing sFRP-1, an inhibitor of the Wnt/β-catenin signaling pathway.Methods: Mice randomized at 1 week post-MI were administered lcz696 (60 mg/kg, n = 21), valsartan (30 mg/kg, n = 19), or corn oil (n = 13) orally for 4 weeks, while the sham-operated group received vehicle (corn oil, n = 19). Cardiac function and extent of myocardial fibrosis were measured. Western blotting and quantitative real-time polymerase chain reaction were used to detect the expression of Wnt/β-catenin pathway-related proteins. Furthermore, primary myocardial fibroblasts were stimulated with angiotensin II (Ang II) and cultured with lcz696 and the sFRP-1 inhibitor way316606 to detect the expression of Wnt/β-catenin pathway proteins.Results: Both lcz696 and valsartan alleviated myocardial fibrosis and improved cardiac function, but lcz696 had superior efficiency compared to valsartan. Furthermore, β-catenin expression was inhibited and sFRP-1 was overexpressed after drug treatment, which could be significantly improved by lcz696 in mice. In addition, lcz696 inhibited β-catenin expression in AngII-stimulated myocardial fibroblasts, and β-catenin expression increased after the inhibition of sFRP-1.Conclusion: ARNI alleviated cardiac fibrosis and cardiac remodeling by inhibiting the Wnt/β-catenin signaling pathway. In addition, ARNI can lead to overexpression of sFRP-1, which is an inhibitor of the Wnt/β-catenin signaling pathway. These results indicate a new therapeutic target of ARNI to improve myocardial fibrosis and prevent myocardial remodeling.

scholarly journals Blockade of the Notch Signaling Pathway Promotes M2 Macrophage Polarization to Suppress Cardiac Fibrosis Remodeling in Mice With Myocardial Infarction

2022 ◽  
Vol 8 ◽  
Author(s):  
Zhi Li ◽  
Miao Nie ◽  
Liming Yu ◽  
Dengshun Tao ◽  
Qiang Wang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Cardiac Fibrosis ◽  
Macrophage Polarization ◽  
Notch Signaling Pathway ◽  
Inflammatory Factors ◽  
M2 Macrophage ◽  
M2 Polarization

Myocardial infarction (MI) is regarded as a serious ischemic heart disease on a global level. The current study set out to explore the mechanism of the Notch signaling pathway in the regulation of fibrosis remodeling after the occurrence of MI. First, experimental mice were infected with recombination signal binding protein J (RBP-J) shRNA and empty adenovirus vector, followed by the establishment of MI mouse models and detection of cardiac function. After 4 weeks of MI, mice in the sh-RBP-J group were found to exhibit significantly improved cardiac function relative to the sh-NC group. Moreover, knockdown of RBP-J brought about decreased infarct area, promoted cardiac macrophages M2 polarization, reduced cardiac fibrosis, and further decreased transcription and protein expressions of inflammatory factors and fibrosis-related factors. Furthermore, downregulation of cylindromatosis (CYLD) using si-CYLD reversed the results that knockdown of RBP-J inhibited fibrogenesis and the release of inflammatory factors. Altogether, our findings indicated that the blockade of Notch signaling promotes M2 polarization of cardiac macrophages and improves cardiac function by inhibiting the imbalance of fibrotic remodeling after MI.

scholarly journals Salvia miltiorrhizaandCarthamus tinctoriusExtract Prevents Cardiac Fibrosis and Dysfunction after Myocardial Infarction by Epigenetically Inhibiting Smad3 Expression

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Jing Yang ◽  
Bo Wang ◽  
Na Li ◽  
Qingqing Zhou ◽  
Wenhui Zhou ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Growth Factor ◽  
Cardiac Function ◽  
Myocardial Fibrosis ◽  
Histone Methylation ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Salvia Miltiorrhiza ◽  
Left Ventricular

The incidence of cardiac dysfunction after myocardial infarction (MI) continues to increase despite advances in treatment. Excessive myocardial fibrosis plays a vital role in the development of adverse cardiac remodeling and deterioration of cardiac function. Understanding the molecular and cellular mechanism of the fibrosis process and developing effective therapeutics are of great importance.Salvia miltiorrhizaandCarthamus tinctoriusextract (SCE) is indicated for angina pectoris and other ischemic cardiovascular diseases in China. SCE has been shown to inhibit the platelet activation and aggregation, ameliorate ROS-induced myocardial necrosis by inhibiting mitochondrial permeability transition pore opening, and promote angiogenesis by upregulating the expression of vascular endothelial growth factor (VEGF). However, whether SCE has effect on cardiac fibrosis after MI is not fully clear. Here, a mouse model of MI was established to observe the effect of SCE upon survival, cardiac function, myocardial fibrosis, and inflammation. Quantitative PCR and western blot assays were used to determine the expression of genes related to transforming growth factor-β(TGF-β) cascade and inflammatory responsesin vivo. Additionally, the effects of SCE upon the collagen production, TGF-β/Smad3 (SMAD family member 3) signaling, and the levels of histone methylation in primary cardiac fibroblasts were detected. We found that SCE treatment significantly improved survival and left ventricular function in mice after MI. Inhibition of inflammation and fibrosis, as well as decreased expression of Smad3, was observed with SCE treatment. In TGF-β-stimulated cardiac fibroblasts, SCE significantly decreased the expression of collagen,α-smooth muscle actin (α-SMA), and Smad3. Furthermore, SCE treatment downregulated the levels of H3K4 trimethylation (H3K4me3) and H3K36 trimethylation (H3K36me3) at theSmad3promoter region of cardiac fibroblasts, leading to inhibition ofSmad3transcription. Our findings suggested that SCE prevents myocardial fibrosis and adverse remodeling after MI with a novel mechanism of suppressing histone methylation of theSmad3promoter and its transcription.

scholarly journals Manuscript title Microparticles Containing MiR-625-5p In Coronary Artery Reduce Myocardial Fibrosis After Myocardial Infarction

2021 ◽  
Author(s):  
Ningxin Wen ◽  
Qi Zhang ◽  
Xuan Wu ◽  
Jianing Gao ◽  
Yangkai Xu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Myocardial Fibrosis ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
High Mobility ◽  
Coronary Intervention ◽  
Thrombus Aspiration ◽  
St Segment Elevation ◽  
Emergency Percutaneous Coronary Intervention

Abstract PurposeBlood from infarct-related arteries obtained by thrombus aspiration is good material for studying the local microenvironment of blood vessels in myocardial infarction. Here, we aimed to observe the effects of intracoronary microparticles (MPs) on cardiac fibrosis and to find associated microRNAs in MPs.MethodsBlood samples were collected from patients with ST-segment elevation myocardial infarction who underwent emergency percutaneous coronary intervention, and sub-supersonic centrifugation was used to separate the MPs.ResultsWe found that rats treated with intracoronary MPs showed better cardiac function after myocardial infarction compared with rats treated with PBS control or peripheral MPs. RNA microarray analysis indicated that microRNAs, especially miR-625-5p, may play a role in the process. Supplementation with miR-625-5p inhibited proliferation of cardiac fibroblasts and myocardial fibrosis in a mouse myocardial infarction model. ConclusionOur findings indicate that plasma MPs in infarct-related arteries in patients with acute myocardial infarction can inhibit myocardial fibrosis and improve cardiac function, with a process mediated by miR-625-5p and HMGA1 (high mobility group AT-hook 1). The current study may provide a possible reference for thrombus aspiration standard.

scholarly journals Methyl Ferulic Acid Attenuates Human Cardiac Fibroblasts Differentiation and Myocardial Fibrosis by Suppressing pRB-E2F1/CCNE2 and RhoA/ROCK2 Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Rongheng Liao ◽  
Zhen Qi ◽  
Ri Tang ◽  
Renrong Wang ◽  
Yongyi Wang
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Ferulic Acid ◽  
Myocardial Fibrosis ◽  
Cardiac Fibroblasts ◽  
Treated Group ◽  
Biologically Active ◽  
Human Cardiac Fibroblasts ◽  
Related Proteins

Background: Myocardial fibrosis is a key pathological process after myocardial infarction, which leads to poor outcomes in patients at the end stage. Effective treatments for improving prognosis of myocardial fibrosis are needed to be further developed. Methyl ferulic acid (MFA), a biologically active monomer extracted and purified from the Chinese herbal medicine, is reported as an attenuator in many diseases. In this study, we aim to reveal the role it plays in myocardial fibrosis after myocardial infarction and its possible mechanism.Results: Firstly, we found that MFA attenuated the expression of fibrosis-related proteins and the ability of migration and proliferation in TGF-β1–induced human cardiac fibroblasts (HCFs). Then, myocardial fibrosis after myocardial infarction models on mouse was built to reveal the in vivo affection of MFA. After 28 days of treatments, fibrosis areas, cardiac function, and expression of fibrosis-related proteins were all improved in the MFA-treated group than the myocardial infarction group. Finally, to elucidate the mechanism of phenomenon we observed, we found that MFA attenuated HCF differentiation after myocardial infarction by suppressing the migration and proliferation in HCFs, which was by suppressing the pRB-E2F1/CCNE2 and the RhoA/ROCK2 pathway.Conclusion: Our findings showed that MFA attenuated the expression of fibrosis-related proteins, and the ability of migration and proliferation in HCFs improved the cardiac function of myocardial infarction mice; meanwhile, the mechanism of that was by suppressing the pRB-E2F1/CCNE2 and the RhoA/ROCK2 pathway.

scholarly journals Astragaloside IV Ameliorates Myocardial Infarction Induced Apoptosis and Restores Cardiac Function

2021 ◽  
Vol 9 ◽  
Author(s):  
Chuang Sun ◽  
Guangwei Zeng ◽  
Tingting Wang ◽  
He Ren ◽  
Huixian An ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Cardiac Fibrosis ◽  
Mapk Signaling ◽  
Diabetic Mice ◽  
Astragaloside Iv ◽  
Induced Apoptosis ◽  
Mapk Signaling Pathways

BackgroundType 2 diabetes mellitus increases the risk of cardiovascular disease including myocardial infarction (MI). Inflammation and apoptosis have been implicated in the pathophysiology of MI. In the present study, the effects of astragaloside IV (AS-IV) on MI in diabetic mice were evaluated.MethodsHigh glucose/high fat (HG/HF) and hypoxia culture condition were established to mimic diabetic condition. After administration of AS-IV to H9c2 myocytes, the cell apoptosis, viability, and activation of mitogen-activated protein kinase (MAPK) signaling pathways were detected. MI was induced in streptozotocin-induced diabetic mice. After administration of AS-IV to mice, cardiac function, cardiac fibrosis, inflammation, and activation of MAPK signaling pathway were detected.ResultsAstragaloside IV treatment significantly inhibited HG/HF and hypoxia-induced apoptosis of H9c2. AS-IV inhibited activation of JNK and p38 signaling pathway while promoting the activation of EKR signaling pathway. AS-IV treatment rescued cardiac function, suppressed cardiac fibrosis and inflammation, and differently regulated the activation of MAPK signaling pathways.ConclusionAstragaloside IV prevented apoptosis and restored cardiac function in MI, which may be due to the regulation of MAPK signaling pathway in diabetes.

Abstract 13810: TT-00920, a Clinical Stage Novel Phosphodiesterase 9 Inhibitor, Protects Against Heart Failure in a Rat Model of Myocardial Infarction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Zejuan Sheng ◽  
Xiaoyan Qiang ◽  
Guoyu Li ◽  
Huimin Wang ◽  
Wenxin Dong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Rat Model ◽  
Cardiac Fibrosis ◽  
Clinical Stage ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Therapeutic Effects ◽  
Dependent Manner

Introduction: Phosphodiesterase 9 (PDE9) controls natriuretic-peptide-stimulated cyclic guanosine monophosphate in cardiac myocytes and is stongly upregulated in human heart failure, suggesting its potential as a promising therapeutic target in heart failure. Here we investigated the potential effects of TT-00920, a clinical stage novel and highly selective PDE9 inhibitor, on heart failure in a rat model of myocardial infarction. Methods: Myocardial infarction was induced by left anterior descending coronary artery (LAD) ligation in male Sprague Dawley rats. After 4-week treatment of vehicle, LCZ696, TT-00920, or TT-00920/Valsartan by oral gavage, efficacy was assessed by echocardiography and cardiac histopathology. Results: TT-00920 had remarkably improved cardiac function, protected against cardiac remodeling and fibrosis in a dose-dependent manner. TT-00920/Valsartan combination showed superior beneficial efficacy when compared to TT-00920 or LCZ696 single agent.Figure 1. TT-00920 improved cardiac function and ventricular remodeling.Figure 2. TT-00920 attenuated cardiac fibrosis in peri-infarct zone. Conclusions: TT-00920 reversed LAD-induced left ventricular dysfunction and remodeling, supporting its potential as a novel therapeutic agent for heart failure. The superior efficacy of TT-00920/Valsartan combination suggests that TT-00920 and renin-angiotensin-aldosterone system inhibitors may have additive therapeutic effects in heart failure.TT-00920 is currently being evaluated in Phase 1 clinical study for safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers (NCT04364789).

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