Cardiac fibroblasts as sentinel cells in cardiac tissue: Receptors, signaling pathways and cellular functions

Díaz‐Araya, Guillermo; Vivar, Raúl; Humeres, Claudio; Boza, Pía; Bolívar, Samir; Muñoz, Claudia

doi:10.1016/j.phrs.2015.07.001

Cited by 63 publications

(36 citation statements)

References 128 publications

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“…In the clinic, TRPM and its mediated Ca 2+ -influx signal in CFs of SSS patients have been shown to play a key role in the transformation of CFs into CMFs [21], which was supported by the findings that TRPM7 contributed to the Ang II-mediated progression of atrial fibrosis through the regulation of influx of Ca 2+ and Mg 2+ [22]. It has been well recognized that the Ang II-mediated TGF-β1/Smad pathway plays an important role in promoting CFs to secrete extracellular matrix and in myocardial collagen deposition [23–25]. The molecular basis underlying how TRPM7 is incorporated into Ang II-mediated TGF-β1/Smad signaling to direct the development of SSS has not been well defined, although one study proposed that TRPM7 was potentially required in TGF-β-induced fibrogenesis in human atrial fibrillation [26] and another study showed that TRPM7 mediated TGF-β1-elicited collagen expression in hepatic stellate cells [27].…”

Section: Introductionmentioning

confidence: 93%

TRPM7 regulates angiotensin II-induced sinoatrial node fibrosis in sick sinus syndrome rats by mediating Smad signaling

et al. 2018

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Sinoatrial node fibrosis is involved in the pathogenesis of sinus sick syndrome (SSS). Transient receptor potential (TRP) subfamily M member 7 (TRPM7) is implicated in cardiac fibrosis. However, the mechanisms underlying the regulation of sinoatrial node (SAN) fibrosis in SSS by TRPM7 remain unknown. The aim of this study was to investigate the role of angiotensin II (Ang II)/TRPM7/Smad pathway in the SAN fibrosis in rats with SSS. The rat SSS model was established with sodium hydroxide pinpoint pressing permeation. Forty-eight rats were randomly divided into six groups: normal control (ctrl), sham operation (sham), postoperative 1-, 2-, 3-, and 4-week SSS, respectively. The tissue explant culture method was used to culture cardiac fibroblasts (CFs) from rat SAN tissues. TRPM7 siRNA or encoding plasmids were used to knock down or overexpress TRPM7. Collagen (Col) distribution in SAN and atria was assessed using PASM–Masson staining. Ang II, Col I, and Col III levels in serum and tissues or in CFs were determined by ELISA. TRPM7, smad2 and p-smad2 levels were evaluated by real-time PCR, and/or western blot and immunohistochemistry. SAN and atria in rats of the SSS groups had more fibers and higher levels of Ang II, Col I and III than the sham rats. Similar findings were obtained for TRPM7 and pSmad2 expression. In vitro, Ang II promoted CFs collagen synthesis in a dose-dependent manner, and potentiated TRPM7 and p-Smad2 expression. TRPM7 depletion inhibited Ang II-induced p-Smad2 expression and collagen synthesis in CFs, whereas increased TRPM7 expression did the opposite. SAN fibrosis is regulated by the Ang II/TRPM7/Smad pathway in SSS, indicating that TRPM7 is a potential target for SAN fibrosis therapy in SSS.

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Section: Introductionmentioning

confidence: 93%

TRPM7 regulates angiotensin II-induced sinoatrial node fibrosis in sick sinus syndrome rats by mediating Smad signaling

et al. 2018

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“…However, CF can also act as “sentinel” cells, detecting changes in chemical and mechanical signals in the heart and stimulating an appropriate response (Frangogiannis, 2007; Van Linthout et al, 2014; Díaz-Araya et al, 2015). Immediately after tissue damage, CF contribute to the inflammation necessary for repair, secreting pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), as well as pro-inflammatory chemokines, such as monocyte chemoattractant protein 1 (MCP-1) and interleukin-8 (Kukielka et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

IFN-β Plays Both Pro- and Anti-inflammatory Roles in the Rat Cardiac Fibroblast Through Differential STAT Protein Activation

et al. 2018

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Cardiac fibroblasts (CFs) contribute to theinflammatory response to tissue damage, secreting both pro- and anti-inflammatory cytokines and chemokines. Interferon beta (IFN-β) induces the phosphorylation of signal transducer and activator of transcription (STAT) proteins through the activation of its own receptor, modulating the secretion of cytokines and chemokines which regulate inflammation. However, the role of IFN-β and STAT proteins in modulating the inflammatory response of CF remains unknown. CF were isolated from adult male rats and subsequently stimulated with IFN-β to evaluate the participation of STAT proteins in secreting chemokines, cytokines, cell adhesion proteins expression and in their capacity to recruit neutrophils. In addition, in CF in which the TRL4 receptor was pre-activated, the effect of INF-β on the aforementioned responses was also evaluated. Cardiac fibroblasts stimulation with IFN-β showed an increase in STAT1, STAT2, and STAT3 phosphorylation. IFN-β stimulation through STAT1 activation increased proinflammatory chemokines MCP-1 and IP-10 secretion, whereas IFN-β induced activation of STAT3 increased cytokine secretion of anti-inflammatory IL-10. Moreover, in TLR4-activated CF, IFN-β through STAT2 and/or STAT3, produced an anti-inflammatory effect, reducing pro-IL-1β, TNF-α, IL-6, MCP-1, and IP-10 secretion; and decreasing neutrophil recruitment by decreasing ICAM-1 and VCAM-1 expression. Altogether, our results indicate that IFN-β exerts both pro-inflammatory and anti-inflammatory effects in non-stimulated CF, through differential activation of STAT proteins. When CF were previously treated with an inflammatory agent such as TLR-4 activation, IFN-β effects were predominantly anti-inflammatory.

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“…How ZYZ-168 mediates these effects became the next focus of this piece of work34. Myofibroblasts are known to secret collagens (such as collagen I, III, IV) that mediate synthesis and repair of the ECM that contributes to the development of scar tissue.…”

Section: Discussionmentioning

confidence: 99%

ZYZ-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of ERK1/2-dependent ROCK1 activation

Luo

Hieu

et al. 2017

Sci Rep

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Selective treatments for myocardial infarction (MI) induced cardiac fibrosis are lacking. In this study, we focus on the therapeutic potential of a synthetic cardio-protective agent named ZYZ-168 towards MI-induced cardiac fibrosis and try to reveal the underlying mechanism. ZYZ-168 was administered to rats with coronary artery ligation over a period of six weeks. Ecocardiography and Masson staining showed that ZYZ-168 substantially improved cardiac function and reduced interstitial fibrosis. The expression of α–smooth muscle actin (α-SMA) and Collagen I were reduced as was the activity of matrix metalloproteinase 9 (MMP-9). These were related with decreased phosphorylation of ERK1/2 and expression of Rho-associated coiled-coil containing protein kinase 1 (ROCK1). In cardiac fibroblasts stimulated with TGF-β1, phenotypic switches of cardiac fibroblasts to myofibroblasts were observed. Inhibition of ERK1/2 phosphorylation or knockdown of ROCK1 expectedly reduced TGF-β1 induced fibrotic responses. ZYZ-168 appeared to inhibit the fibrotic responses in a concentration dependent manner, in part via a decrease in ROCK 1 expression through inhibition of the phosphorylation status of ERK1/2. For inhibition of ERK1/2 phosphorylation with a specific inhibitor reduced the activation of ROCK1. Considering its anti-apoptosis activity in MI, ZYZ-168 may be a potential drug candidate for treatment of MI-induced cardiac fibrosis.

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Cardiac fibroblasts as sentinel cells in cardiac tissue: Receptors, signaling pathways and cellular functions

Cited by 63 publications

References 128 publications

TRPM7 regulates angiotensin II-induced sinoatrial node fibrosis in sick sinus syndrome rats by mediating Smad signaling

TRPM7 regulates angiotensin II-induced sinoatrial node fibrosis in sick sinus syndrome rats by mediating Smad signaling

IFN-β Plays Both Pro- and Anti-inflammatory Roles in the Rat Cardiac Fibroblast Through Differential STAT Protein Activation

ZYZ-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of ERK1/2-dependent ROCK1 activation

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