Crosstalk Between the Activated Slit2-Robo1 Pathway and TGF-β1 Signalling Promotes Cardiac Fibrosis

Overview

Journal ESC Heart Fail

Date 2020 Nov 25

PMID 33236535

Citations 18

Authors

Yunqi Liu

Ziwei Yin

Xueqin Xu

Chen Liu

Xiaoying Duan

Qinlan Song

Ying Tuo

Cuiping Wang

Jing Yang

Shengli Yin

Affiliations

Soon will be listed here.

Abstract

Aims: Previous reports indicated that the Slit2-Robo signalling pathway is involved in embryonic heart development and fibrosis in other solid organs, but its function in adult cardiac fibrosis has not been investigated. Here, we investigate the role of the Slit2-Robo1 signalling pathway in cardiac fibrosis.

Methods And Results: The right atrial tissue samples were obtained from patients with valvular heart disease complicated by atrial fibrillation during heart valve surgery and from healthy heart donors. The fibrotic animal model is created by performing transverse aortic constriction (TAC) surgery. The Robo1, Slit2, TGF-β1, and collagen I expression levels in human and animal samples were evaluated by immunohistochemistry and western blot analysis. Echocardiography measured the changes in heart size and cardiac functions of animals. Angiotensin II (Ang II), Slit2-siRNA, TGF-β1-siRNA, recombinant Slit2, and recombinant TGF-β1 were transfected to cardiac fibroblasts (CFs) respectively to observe their effects on collagen I expression level. The right atrial appendage of patients with valvular heart disease complicated by atrial fibrillation found significantly up-regulated Slit2, Robo1, TGF-β1, and collagen I expression levels. TAC surgery leads to heart enlargement, cardiac fibrosis, and up-regulation of Slit2, Robo1, TGF-β1, and collagen I expression levels in animal model. Robo1 antagonist R5 and TGF-β1 antagonist SB431542 suppressed cardiac fibrosis in TAC mice. Treatment with 100 nM Ang II in CFs caused significantly increased Slit2, Robo1, Smad2/3, TGF-β1, collagen I, PI3K, and Akt expression levels. Transfecting Slit2-siRNA and TGF-β1-siRNA, respectively, into rat CFs significantly down-regulated Smad2/3 and collagen I expression, inhibiting the effects of Ang II. Recombinant Slit2 activated the TGF-β1/Smad signalling pathway in CFs and up-regulated Periostin, Robo1, and collagen I expression.

Conclusions: The Slit2-Robo1 signalling pathway interfered with the TGF-β1/Smad pathway and promoted cardiac fibrosis. Blockade of Slit2-Robo1 might be a new treatment for cardiac fibrosis.

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References

Song S, Liu L, Yu Y, Zhang R, Li Y, Cao W . Inhibition of BRD4 attenuates transverse aortic constriction- and TGF-β-induced endothelial-mesenchymal transition and cardiac fibrosis. J Mol Cell Cardiol. 2018; 127:83-96. DOI: 10.1016/j.yjmcc.2018.12.002. View

Liu Y, Yin Z, Xu X, Liu C, Duan X, Song Q . Crosstalk between the activated Slit2-Robo1 pathway and TGF-β1 signalling promotes cardiac fibrosis. ESC Heart Fail. 2020; 8(1):447-460. PMC: 7835586. DOI: 10.1002/ehf2.13095. View

Dixon I, Landry N, Rattan S . Periostin Reexpression in Heart Disease Contributes to Cardiac Interstitial Remodeling by Supporting the Cardiac Myofibroblast Phenotype. Adv Exp Med Biol. 2019; 1132:35-41. DOI: 10.1007/978-981-13-6657-4_4. View

Davis J, Salomonis N, Ghearing N, Lin S, Kwong J, Mohan A . MBNL1-mediated regulation of differentiation RNAs promotes myofibroblast transformation and the fibrotic response. Nat Commun. 2015; 6:10084. PMC: 4703843. DOI: 10.1038/ncomms10084. View

Tomasoni D, Adamo M, Lombardi C, Metra M . Highlights in heart failure. ESC Heart Fail. 2020; 6(6):1105-1127. PMC: 6989277. DOI: 10.1002/ehf2.12555. View

Gourdie R, Dimmeler S, Kohl P . Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease. Nat Rev Drug Discov. 2016; 15(9):620-638. PMC: 5152911. DOI: 10.1038/nrd.2016.89. View

Yao Y, Zhou Z, Li L, Li J, Huang L, Li J . Activation of Slit2/Robo1 Signaling Promotes Tumor Metastasis in Colorectal Carcinoma through Activation of the TGF-β/Smads Pathway. Cells. 2019; 8(6). PMC: 6628122. DOI: 10.3390/cells8060635. View

Platonov P, Mitrofanova L, Orshanskaya V, Ho S . Structural abnormalities in atrial walls are associated with presence and persistency of atrial fibrillation but not with age. J Am Coll Cardiol. 2011; 58(21):2225-32. DOI: 10.1016/j.jacc.2011.05.061. View

Khalil H, Kanisicak O, Prasad V, Correll R, Fu X, Schips T . Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest. 2017; 127(10):3770-3783. PMC: 5617658. DOI: 10.1172/JCI94753. View

10.

Wijffels M, Kirchhof C, Dorland R, Allessie M . Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation. 1995; 92(7):1954-68. DOI: 10.1161/01.cir.92.7.1954. View

11.

Meagher P, Adam M, Connelly K . It's Not All About the Cardiomyocyte: Fibroblasts, Empagliflozin, and Cardiac Remodelling. Can J Cardiol. 2020; 36(4):464-466. DOI: 10.1016/j.cjca.2019.10.017. View

12.

Zhao J, Mommersteeg M . Slit-Robo signalling in heart development. Cardiovasc Res. 2018; 114(6):794-804. PMC: 5909645. DOI: 10.1093/cvr/cvy061. View

13.

Kaneko T, Nomura F, Yasuda K . On-chip constructive cell-network study (I): contribution of cardiac fibroblasts to cardiomyocyte beating synchronization and community effect. J Nanobiotechnology. 2011; 9:21. PMC: 3123623. DOI: 10.1186/1477-3155-9-21. View

14.

Chou C, Hung C, Liao C, Wei L, Chen C, Shun C . IL-6 trans-signalling contributes to aldosterone-induced cardiac fibrosis. Cardiovasc Res. 2018; 114(5):690-702. DOI: 10.1093/cvr/cvy013. View

15.

Zhang Y, Huang X, Wei L, Chung A, Yu C, Lan H . miR-29b as a therapeutic agent for angiotensin II-induced cardiac fibrosis by targeting TGF-β/Smad3 signaling. Mol Ther. 2014; 22(5):974-85. PMC: 4015231. DOI: 10.1038/mt.2014.25. View

16.

Nagata S, Varagic J, Kon N, Wang H, Groban L, Simington S . Differential expression of the angiotensin-(1-12)/chymase axis in human atrial tissue. Ther Adv Cardiovasc Dis. 2015; 9(4):168-80. PMC: 5823505. DOI: 10.1177/1753944715589717. View

17.

Lal H, Ahmad F, Zhou J, Yu J, Vagnozzi R, Guo Y . Cardiac fibroblast glycogen synthase kinase-3β regulates ventricular remodeling and dysfunction in ischemic heart. Circulation. 2014; 130(5):419-30. PMC: 4153405. DOI: 10.1161/CIRCULATIONAHA.113.008364. View

18.

Qiu H, Wu H, Ma J, Cao H, Huang L, Qiu W . DL-3-n-Butylphthalide reduces atrial fibrillation susceptibility by inhibiting atrial structural remodeling in rats with heart failure. Naunyn Schmiedebergs Arch Pharmacol. 2018; 391(3):323-334. DOI: 10.1007/s00210-017-1457-1. View

19.

Tao L, Bei Y, Chen P, Lei Z, Fu S, Zhang H . Crucial Role of miR-433 in Regulating Cardiac Fibrosis. Theranostics. 2016; 6(12):2068-2083. PMC: 5039681. DOI: 10.7150/thno.15007. View

20.

Kim H, Hong Y, Park H, Ahn Y, Jeong M . Effects of Ivabradine on Left Ventricular Systolic Function and Cardiac Fibrosis in Rat Myocardial Ischemia-Reperfusion Model. Chonnam Med J. 2018; 54(3):167-172. PMC: 6165924. DOI: 10.4068/cmj.2018.54.3.167. View