Low-density lipoprotein receptor-related protein 6 regulates cardiomyocyte-derived paracrine signaling to ameliorate cardiac fibrosis

Wang, Xiang; Zou, Yutong; Chen, Zhidan; Li, Yang; Pan, Le; Wang, Ying; Liu, Ming; Yin, Chao; Wu, Jian; Yang, Chunjie; Zhang, Lei; Li, Chenze; Huang, Zheyong; Wang, Daowen; Qian, Juying; Zou, Yunzeng; Gong, Hui

doi:10.7150/thno.48787

Cited by 9 publications

(7 citation statements)

References 44 publications

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“…Wnt proteins bind to a receptor complex composed of a Frizzled (FZD) receptor and a low-density lipoprotein receptor-related protein 5/6 (LRP5/6), to initiate signaling in different intracellular responses, involving β-catenin (canonical Wnt pathway), Ca 2+ , or other second messengers (non-canonical Wnt pathways) [3,4]. We recently observed cardiac-specific LRP6 overexpression suppressed cardiac fibrosis and inhibited the secretion and expression of Wnt5a and Wnt11 in CMs under pressure overload [5]. Wnt5a and Wnt11, two non-canonical Wnt ligands, are co-required to promote second heart field development by restraining Wnt/β-catenin signaling in mice [6].…”

Section: Introductionmentioning

confidence: 99%

Cardiac Wnt5a and Wnt11 promote fibrosis by the crosstalk of FZD5 and EGFR signaling under pressure overload

et al. 2021

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Progressive cardiac fibrosis accelerates the development of heart failure. Here, we aimed to explore serum Wnt5a and Wnt11 levels in hypertension patients, the roles of Wnt5a and Wnt11 in cardiac fibrosis and potential mechanisms under pressure overload. The pressure overload mouse model was built by transverse aortic constriction (TAC). Cardiac fibrosis was analyzed by Masson’s staining. Serum Wnt5a or Wnt11 was elevated and associated with diastolic dysfunction in hypertension patients. TAC enhanced the expression and secretion of Wnt5a or Wnt11 from cardiomyocytes (CMs), cardiac fibroblasts (CFs), and cardiac microvascular endothelial cells (CMECs). Knockdown of Wnt5a and Wnt11 greatly improved cardiac fibrosis and function at 4 weeks after TAC. In vitro, shWnt5a or shWnt11 lentivirus transfection inhibited pro-fibrotic effects in CFs under mechanical stretch (MS). Similarly, conditional medium from stretched-CMs transfected with shWnt5a or shWnt11 lentivirus significantly suppressed the pro-fibrotic effects induced by conditional medium from stretched-CMs. These data suggested that CMs- or CFs-derived Wnt5a or Wnt11 showed a pro-fibrotic effect under pressure overload. In vitro, exogenous Wnt5a or Wnt11 activated ERK and p38 (fibrotic-related signaling) pathway, promoted the phosphorylation of EGFR, and increased the expression of Frizzled 5 (FZD5) in CFs. Inhibition or knockdown of EGFR greatly attenuated the increased FZD5, p-p38, and p-ERK levels, and the pro-fibrotic effect induced by Wnt5a or Wnt11 in CFs. Si-FZD5 transfection suppressed the increased p-EGFR level, and the fibrotic-related effects in CFs treated with Wnt5a or Wnt11. In conclusion, pressure overload enhances the secretion of Wnt5a or Wnt11 from CMs and CFs which promotes cardiac fibrosis by activation the crosstalk of FZD5 and EGFR. Thus, Wnt5a or Wnt11 may be a novel therapeutic target for the prevention of cardiac fibrosis under pressure overload.

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Section: Introductionmentioning

confidence: 99%

Cardiac Wnt5a and Wnt11 promote fibrosis by the crosstalk of FZD5 and EGFR signaling under pressure overload

et al. 2021

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“…In this study, our data displayed that the regulation of the MIAT/miR‐488‐3p/Wnt/β‐catenin pathway in the inflammation of hypoxia‐treated AC16 cells: MIAT depletion suppressed the production of proinflammatory cytokines (IL‐1β, TNF‐α, and IL‐6), and this effect was partly abated via miR‐488‐3p downregulation or Wnt5a restoration; Wnt5a upregulation partly overturned miR‐488‐3p overexpression‐mediated IL‐1β, TNF‐α, and IL‐6 production suppression in AC16 cells (Supporting Information: Figure 6). Additionally, previous studies have suggested that Wnt signaling was associated with cardiac fibrosis in cardiac diseases (X. Wang, Zou, et al, 2021; Yousefi et al, 2020). Meanwhile, Wnt5a has been reported to promote cardiac fibrosis in myocardial infarction (Bai et al, 2020; X. Wang, Zou, et al, 2021).…”

Section: Discussionmentioning

confidence: 94%

“…Additionally, previous studies have suggested that Wnt signaling was associated with cardiac fibrosis in cardiac diseases (X. Wang, Zou, et al, 2021;Yousefi et al, 2020). Meanwhile, Wnt5a has been reported to promote cardiac fibrosis in myocardial infarction (Bai et al, 2020;X.…”

Section: Restoration Of Wnt5a Alleviates the Effect Of Miat Knockdown...mentioning

confidence: 98%

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Knockdown of long noncoding RNA MIAT attenuates hypoxia‐induced cardiomyocyte injury by regulating the miR‐488‐3p/Wnt/β‐catenin pathway

Zhang

et al. 2022

Cell Biology International

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Dysfunction of cardiomyocytes contributes to the development of acute myocardial infarction (AMI). Nonetheless, the regulatory mechanism of lncRNA myocardial infarction-associated transcript (MIAT) in cardiomyocyte injury remains largely unclear. The cardiomyocyte injury was assessed via cell viability and apoptosis using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) and flow cytometry, respectively. The levels of MIAT, microRNA (miR)-488-3p, and Wnt5a were detected via quantitative real-time polymerase chain reaction and Western blot.After bioinformatical analysis, the binding between miR-488-3p and MIAT or Wnt5a was confirmed via dual-luciferase reporter, RNA immunoprecipitation, and RNA pulldown assays. Our results showed that MIAT expression was increased in AC16 cells after hypoxia treatment. Silencing of MIAT alleviated hypoxia-induced viability reduction, apoptosis increase, and Wnt/β-catenin pathway activation. MIAT directly targeted miR-488-3p. MiR-488-3p might repress hypoxia-induced cardiomyocyte injury, and its knockdown reversed the effect of MIAT depletion on cardiomyocyte injury. Wnt5a was validated as a target of miR-488-3p. Wnt5a expression restoration attenuated the influence of MIAT knockdown on hypoxia-triggered cardiomyocyte injury. Our findings demonstrated that downregulation of MIAT might mitigate hypoxia-induced cardiomyocyte injury partly through miR-488-3p mediated Wnt/β-catenin pathway.

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“…As a result, cardiomyocyte-secreted Wnt5a/Wnt11 was reduced, and cardiac fibrosis was eventually attenuated. 263 In the pressure overload model, Wnt/β-catenin signaling was activated. Cardiac fibroblast-specific loss of β-catenin preserved heart function and alleviated cardiac hypertrophy and fibrosis under TAC by downregulating the expression of collagen genes downstream of TGF-β signaling.…”

Section: Signaling Cascades In Failing Heartmentioning

confidence: 99%

Signaling cascades in the failing heart and emerging therapeutic strategies

Long

et al. 2022

Sig Transduct Target Ther

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Chronic heart failure is the end stage of cardiac diseases. With a high prevalence and a high mortality rate worldwide, chronic heart failure is one of the heaviest health-related burdens. In addition to the standard neurohormonal blockade therapy, several medications have been developed for chronic heart failure treatment, but the population-wide improvement in chronic heart failure prognosis over time has been modest, and novel therapies are still needed. Mechanistic discovery and technical innovation are powerful driving forces for therapeutic development. On the one hand, the past decades have witnessed great progress in understanding the mechanism of chronic heart failure. It is now known that chronic heart failure is not only a matter involving cardiomyocytes. Instead, chronic heart failure involves numerous signaling pathways in noncardiomyocytes, including fibroblasts, immune cells, vascular cells, and lymphatic endothelial cells, and crosstalk among these cells. The complex regulatory network includes protein–protein, protein–RNA, and RNA–RNA interactions. These achievements in mechanistic studies provide novel insights for future therapeutic targets. On the other hand, with the development of modern biological techniques, targeting a protein pharmacologically is no longer the sole option for treating chronic heart failure. Gene therapy can directly manipulate the expression level of genes; gene editing techniques provide hope for curing hereditary cardiomyopathy; cell therapy aims to replace dysfunctional cardiomyocytes; and xenotransplantation may solve the problem of donor heart shortages. In this paper, we reviewed these two aspects in the field of failing heart signaling cascades and emerging therapeutic strategies based on modern biological techniques.

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Low-density lipoprotein receptor-related protein 6 regulates cardiomyocyte-derived paracrine signaling to ameliorate cardiac fibrosis

Cited by 9 publications

References 44 publications

Cardiac Wnt5a and Wnt11 promote fibrosis by the crosstalk of FZD5 and EGFR signaling under pressure overload

Cardiac Wnt5a and Wnt11 promote fibrosis by the crosstalk of FZD5 and EGFR signaling under pressure overload

Knockdown of long noncoding RNA MIAT attenuates hypoxia‐induced cardiomyocyte injury by regulating the miR‐488‐3p/Wnt/β‐catenin pathway

Signaling cascades in the failing heart and emerging therapeutic strategies

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