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Angiotensin II receptor 1 controls profibrotic Wnt/β-catenin signalling in experimentalautoimmune myocarditis


Czepiel, Marcin; Diviani, Dario; Jaźwa-Kusior, Agnieszka; Tkacz, Karolina; Rolski, Filip; Smolenski, Ryszard T; Siedlar, Maciej; Eriksson, Urs; Kania, Gabriela; Błyszczuk, Przemysław (2022). Angiotensin II receptor 1 controls profibrotic Wnt/β-catenin signalling in experimentalautoimmune myocarditis. Cardiovascular Research, 118(2):573-584.

Abstract

AIMS

Angiotensin (Ang) II signalling has been suggested to promote cardiac fibrosis in inflammatory heart diseases, however the underlaying mechanisms remain obscure. Using Agtr1a-/- mice with genetic deletion of angiotensin receptor type 1 (ATR1) and the experimental autoimmune myocarditis (EAM) model, we aimed to elucidate the role of Ang II-ATR1 pathway in development of heart-specific autoimmunity and post-inflammatory fibrosis.

METHODS AND RESULTS

EAM was induced in wild-type (WT) and Agtr1a-/- mice by subcutaneous injections with alpha myosin heavy chain peptide emulsified in complete Freund's adjuvant. Agtr1a-/- mice developed myocarditis to a similar extent as WT controls at day 21, but showed reduced fibrosis and better systolic function at day 40. Crisscross bone marrow chimera experiments proved that ATR1 signalling in the bone-marrow compartment was critical for cardiac fibrosis. Heart infiltrating, bone-marrow derived cells produced Ang II, but lack of ATR1 in these cells reduced transforming growth factor beta (TGF-β) mediated fibrotic responses. At the molecular level, Agtr1a-/- heart-inflammatory cells showed impaired TGF-β-mediated phosphorylation of Smad2 and TAK1. In WT cells, TGF-β induced formation of RhoA-GTP and RhoA-A-kinase anchoring protein-Lbc (AKAP-Lbc) complex. In Agtr1a-/- cells stabilization of RhoA-GTP and interaction of RhoA with AKAP-Lbc were largely impaired. Furthermore, in contrast to WT cells, Agtr1a-/- cells stimulated with TGF-β failed to activate canonical Wnt pathway indicated by suppressed activity of glycogen synthase kinase-3 (GSK-3)β and nuclear β-catenin translocation and showed reduced expression of Wnts. In line with these in vitro findings, β-catenin was detected in inflammatory regions of hearts of WT, but not Agtr1a-/- mice and expression of canonical Wnt1 and Wnt10b were lower in Agtr1a-/- hearts.

CONCLUSIONS

Ang II-ATR1 signalling is critical for development of postinflammatory fibrotic remodelling and dilated cardiomyopathy. Our data underpins the importance of Ang II-ATR1 in effective TGF-β downstream signalling response including activation of profibrotic Wnt/β-catenin pathway.

TRANSLATIONAL PERSPECTIVE

Myocardial fibrosis causes impaired cardiac function in inflammatory heart diseases. It has been believed that targeting angiotensin II receptor 1 (ATR1) could not only lower blood pressure, but also effectively block both, immune and fibrotic processes in the heart. By using an experimental autoimmune myocarditis model and ATR1-deficient mice, we show that the specific ATR-dependent mechanism is rather limited to control profibrotic, but not inflammatory response. On the molecular level, ATR1 plays a central role in activation of the canonical Wnt pathway in profibrotic response. Thus, these data help to understand how the actual angiotensin II-ATR1 signalling contributes to immunofibrotic heart diseases.

Abstract

AIMS

Angiotensin (Ang) II signalling has been suggested to promote cardiac fibrosis in inflammatory heart diseases, however the underlaying mechanisms remain obscure. Using Agtr1a-/- mice with genetic deletion of angiotensin receptor type 1 (ATR1) and the experimental autoimmune myocarditis (EAM) model, we aimed to elucidate the role of Ang II-ATR1 pathway in development of heart-specific autoimmunity and post-inflammatory fibrosis.

METHODS AND RESULTS

EAM was induced in wild-type (WT) and Agtr1a-/- mice by subcutaneous injections with alpha myosin heavy chain peptide emulsified in complete Freund's adjuvant. Agtr1a-/- mice developed myocarditis to a similar extent as WT controls at day 21, but showed reduced fibrosis and better systolic function at day 40. Crisscross bone marrow chimera experiments proved that ATR1 signalling in the bone-marrow compartment was critical for cardiac fibrosis. Heart infiltrating, bone-marrow derived cells produced Ang II, but lack of ATR1 in these cells reduced transforming growth factor beta (TGF-β) mediated fibrotic responses. At the molecular level, Agtr1a-/- heart-inflammatory cells showed impaired TGF-β-mediated phosphorylation of Smad2 and TAK1. In WT cells, TGF-β induced formation of RhoA-GTP and RhoA-A-kinase anchoring protein-Lbc (AKAP-Lbc) complex. In Agtr1a-/- cells stabilization of RhoA-GTP and interaction of RhoA with AKAP-Lbc were largely impaired. Furthermore, in contrast to WT cells, Agtr1a-/- cells stimulated with TGF-β failed to activate canonical Wnt pathway indicated by suppressed activity of glycogen synthase kinase-3 (GSK-3)β and nuclear β-catenin translocation and showed reduced expression of Wnts. In line with these in vitro findings, β-catenin was detected in inflammatory regions of hearts of WT, but not Agtr1a-/- mice and expression of canonical Wnt1 and Wnt10b were lower in Agtr1a-/- hearts.

CONCLUSIONS

Ang II-ATR1 signalling is critical for development of postinflammatory fibrotic remodelling and dilated cardiomyopathy. Our data underpins the importance of Ang II-ATR1 in effective TGF-β downstream signalling response including activation of profibrotic Wnt/β-catenin pathway.

TRANSLATIONAL PERSPECTIVE

Myocardial fibrosis causes impaired cardiac function in inflammatory heart diseases. It has been believed that targeting angiotensin II receptor 1 (ATR1) could not only lower blood pressure, but also effectively block both, immune and fibrotic processes in the heart. By using an experimental autoimmune myocarditis model and ATR1-deficient mice, we show that the specific ATR-dependent mechanism is rather limited to control profibrotic, but not inflammatory response. On the molecular level, ATR1 plays a central role in activation of the canonical Wnt pathway in profibrotic response. Thus, these data help to understand how the actual angiotensin II-ATR1 signalling contributes to immunofibrotic heart diseases.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:29 January 2022
Deposited On:02 Mar 2021 14:57
Last Modified:24 Jun 2024 01:48
Publisher:Oxford University Press
ISSN:0008-6363
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/cvr/cvab039
PubMed ID:33576779
  • Content: Accepted Version