Genetic Regulation of Fibroblast Activation and Proliferation in Cardiac Fibrosis

Park, Shuin; Ranjbarvaziri, Sara; Lay, Fides D.; Zhao, Peng; Miller, Mark J.; Dhaliwal, Jasmeet; Huertas‐Vazquez, Adriana; Wu, Xinhui; Qiao, Rong; Soffer, Justin M.; Rau, Christoph; Wang, Yibin; Mikkola, Hanna; Lusis, Aldons J.; Ardehali, Reza

doi:10.1161/circulationaha.118.035420

Cited by 58 publications

(37 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6 As a matter of fact, myocardial fibrosis is the end-points of cell differentiation, activation and proliferation of cardiac fibroblasts. 33,34 Our study firstly explains the molecular mechanism by how TGF-β induces cell differentiation of cardiac fibroblasts in myocardial remodelling through Prrx2 up-regulation. As concerned to why Prrx2 F I G U R E 5 Cell differentiation induced by TGF-β is abolished by gene silence of Prrx2 in cardiac fibroblasts.…”

Section: F I G U R E 4 Tgf-β Induces Cell Differentiation and Up-regumentioning

confidence: 99%

Up‐regulation of paired‐related homeobox 2 promotes cardiac fibrosis in mice following myocardial infarction by targeting of Wnt5a

Bai

Tang

Shan

et al. 2019

J Cellular Molecular Medi

View full text Add to dashboard Cite

Cardiac fibrosis is a key factor to determine the prognosis in patient with myocardial infarction (MI). The aim of this study is to investigate whether the transcriptional factor paired-related homeobox 2 (Prrx2) regulates Wnt5a gene expression and the role in myocardial fibrosis following MI. The MI surgery was performed by ligation of left anterior descending coronary artery. Cardiac remodelling was assessed by measuring interstitial fibrosis performed with Masson staining. Cell differentiation was examined by analysis the expression of alpha-smooth muscle actin (α-SMA). Both Prrx2 and Wnt5a gene expressions were up-regulated in mice following MI, accompanied with increased mRNA and protein levels of α-SMA, collagen I and collagen III, compared to mice with sham surgery. Adenovirus-mediated gene knock down of Prrx2 increased survival rate, alleviated cardiac fibrosis, decreased infarction sizes and improved cardiac functions in mice with MI. Importantly, inhibition of Prrx2 suppressed ischaemia-induced Wnt5a gene expression and Wnt5a signalling. In cultured cardiac fibroblasts, TGF-β increased gene expressions of Prrx2 and Wnt5a, and induced cell differentiations, which were abolished by gene silence of either Prrx2 or Wnt5a. S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Bai W-W, Tang Z-Y, Shan T-C, et al. Up-regulation of paired-related homeobox 2 promotes cardiac fibrosis in mice following myocardial infarction by targeting of Wnt5a.

show abstract

Section: F I G U R E 4 Tgf-β Induces Cell Differentiation and Up-regumentioning

confidence: 99%

Up‐regulation of paired‐related homeobox 2 promotes cardiac fibrosis in mice following myocardial infarction by targeting of Wnt5a

Bai

Tang

Shan

et al. 2019

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…Further mechanistic studies revealed that the YAP pathway is an important signaling branch downstream of angiotensin II type 1 receptor in CF mechanotransduction. Cardiac fibroblasts (CFs), a major cell type in the heart, play an important role in maintaining the normal function of the heart (Kong et al, 2019;Park et al, 2018). In response to abnormal changes in biochemical cues (e.g., angiotensin II, interleukin-6, transforming growth factor-β1 ) in various cardiovascular diseases, CFs can be activated into myofibroblasts to initiate a 'reparative' fibrosis.…”

mentioning

confidence: 99%

Matrix stiffness controls cardiac fibroblast activation through regulating YAP via AT₁R

Niu

Jia

et al. 2020

Journal Cellular Physiology

View full text Add to dashboard Cite

Cardiac fibrosis is a common pathway leading to heart failure and involves continued activation of cardiac fibroblasts (CFs) into myofibroblasts during myocardium damage, causing excessive deposition of the extracellular matrix (ECM) and thus increases matrix stiffness. Increasing evidence has shown that stiffened matrix plays an important role in promoting CF activation and cardiac fibrosis, and several signaling factors mediating CF mechanotransduction have been identified. However, the key molecules that perceive matrix stiffness to regulate CF activation remain to be further explored. Here, we detected significantly increased expression and nuclear localization of Yes‐associated protein (YAP) in native fibrotic cardiac tissues. By using mechanically regulated in vitro cell culture models, we found that a stiff matrix‐induced high expression and nuclear localization of YAP in CFs, accompanied by enhanced cell activation. We also demonstrated that YAP knockdown decreased fibrogenic response of CFs and that YAP overexpression promoted CF activation, indicating that YAP plays an important role in mediating matrix stiffness‐induced CF activation. Further mechanistic studies revealed that the YAP pathway is an important signaling branch downstream of angiotensin II type 1 receptor in CF mechanotransduction. The findings help elucidate the mechanism of fibrotic mechanotransduction and may contribute to the development of new approaches for treating fibrotic diseases.

show abstract

“…EPRS is induced by ISO infusion and TAC surgery in vivo as well as by stimulation of ISO, Ang II, TGF-b or IL-11 in vitro. Importantly, one study also showed that Eprs mRNA expression is induced by 1.29-fold in C57BL/6J and 1.42-fold in C3H/HeJ mouse strains on day 14 after ISO infusion 32 . Taken together, we believe that EPRS is one of the major regulators involved in TGF-b-, IL-11-, and ISO-driven translational activation of ECM protein synthesis in cardiac fibroblasts.…”

Section: Discussionmentioning

confidence: 96%

“…The steady-state mRNA expression, translation efficiency, and steady-state protein expression are reduced for the major EPRS preferential target genes from the top 5 GO pathways ( Figure 6C). Among these EPRS targets, LTBP2 (latent TGF-b-binding protein 2) has been recently discovered as an ISO-induced fibrosis marker protein 32 and shown in our screen as downregulated at steadystate mRNA and polysome associated mRNA levels in Halo-treated mouse fibroblasts ( Figure S6B). Mouse LTBP2 protein bears 17 PRR motifs (human LTBP2 has 20 PRR motifs) such as PPP and PPG (supplemental sequence information).…”

Section: Sulf1 and Ltbp2 Are Novel Eprs Downstream Effectorsmentioning

confidence: 88%

EPRS Regulates Proline-rich Pro-fibrotic Protein Synthesis during Cardiac Fibrosis

Subbaiah

Xie

et al. 2019

Preprint

View full text Add to dashboard Cite

Rationale: Increased protein synthesis of pro-fibrotic genes is a common feature of cardiac fibrosis, a major manifestation of heart failure. Despite this important observation, critical factors and molecular mechanisms for translational control of pro-fibrotic genes during cardiac fibrosis remain unclear.Objective: This study aimed to test the hypothesis that cardiac stress-induced expression of a bifunctional aminoacyl-tRNA synthetase (ARS), glutamyl-prolyl-tRNA synthetase (EPRS), is preferentially required for the translation of proline codon-rich (PRR) pro-fibrotic mRNAs in cardiac fibroblasts during cardiac fibrosis. Methods and Results: By analyses of multiple available unbiased large-scale screening datasets of human and mouse heart failure, we have discovered that EPRS acts as an integrated node among all the ARSs in various cardiac pathogenic processes. We confirmed that EPRS was induced at both mRNA and protein level (~1.5-2.5 fold increase) in failing hearts compared with non-failing hearts using our cohort of human and mouse heart samples. Genetic knockout of one allele of Eprs globally (Eprs +/-) using CRISPR-Cas9 technology or in a myofibroblast-specific manner (Eprs flox/+ ; Postn MCM/+ ) strongly reduces cardiac fibrosis (~50% reduction) in isoproterenol-and transverse aortic constriction-induced heart failure mouse models. Inhibition of EPRS by a prolyl-tRNA synthetase (PRS)-specific inhibitor, halofuginone (Halo), significantly decreased the translation efficiency of proline-rich collagens in cardiac fibroblasts. Furthermore, using transcriptome-wide RNA-Seq and polysome profiling-Seq in Halo-treated fibroblasts, we identified multiple novel Pro-rich genes in addition to collagens, such as Ltbp2 and Sulf1, which are translationally regulated by EPRS. As a major EPRS downstream effector, SULF1 is highly enriched in human and mouse myofibroblast. siRNA-mediated knockdown of SULF1 attenuates cardiac myofibroblast activation and collagen deposition. Conclusions:Our results indicate that EPRS preferentially controls the translational activation of proline codon-rich pro-fibrotic genes in cardiac fibroblasts and augments pathological cardiac remodeling.

show abstract

Genetic Regulation of Fibroblast Activation and Proliferation in Cardiac Fibrosis

Cited by 58 publications

References 26 publications

Up‐regulation of paired‐related homeobox 2 promotes cardiac fibrosis in mice following myocardial infarction by targeting of Wnt5a

Up‐regulation of paired‐related homeobox 2 promotes cardiac fibrosis in mice following myocardial infarction by targeting of Wnt5a

Matrix stiffness controls cardiac fibroblast activation through regulating YAP via AT₁R

EPRS Regulates Proline-rich Pro-fibrotic Protein Synthesis during Cardiac Fibrosis

Contact Info

Product

Resources

About

Genetic Regulation of Fibroblast Activation and Proliferation in Cardiac Fibrosis

Cited by 58 publications

References 26 publications

Up‐regulation of paired‐related homeobox 2 promotes cardiac fibrosis in mice following myocardial infarction by targeting of Wnt5a

Up‐regulation of paired‐related homeobox 2 promotes cardiac fibrosis in mice following myocardial infarction by targeting of Wnt5a

Matrix stiffness controls cardiac fibroblast activation through regulating YAP via AT1R

EPRS Regulates Proline-rich Pro-fibrotic Protein Synthesis during Cardiac Fibrosis

Contact Info

Product

Resources

About

Matrix stiffness controls cardiac fibroblast activation through regulating YAP via AT₁R