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Thromb Haemost 2014; 111(04): 736-747
DOI: 10.1160/TH13-06-0448
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Treatment with Angiotensin-(1–7) reduces inflammation in carotid atherosclerotic plaques

Rodrigo A. Fraga-Silva
1   Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
,
Silvia Q. Savergnini
1   Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
,
Fabrizio Montecucco
2   Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland
3   First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
,
Alessio Nencioni
3   First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
,
Irene Caffa
3   First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
,
Debora Soncini
3   First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
,
Fabiana P. Costa-Fraga
1   Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
,
Frederico B. De Sousa
4   Department of Chemistry, Federal University of Minas Gerais, Brazil
,
Ruben D. Sinisterra
4   Department of Chemistry, Federal University of Minas Gerais, Brazil
,
Luciano A. S. Capettini
1   Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
,
Sébastien Lenglet
2   Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland
,
Katia Galan
2   Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland
,
Graziano Pelli
2   Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland
,
Maria Bertolotto
3   First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
,
Aldo Pende
3   First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
,
Giovanni Spinella
5   Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy
,
Bianca Pane
5   Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy
,
Franco Dallegri
3   First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
,
Domenico Palombo
5   Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy
,
François Mach
2   Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland
,
Nikolaos Stergiopulos
1   Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
,
Robson A. S. Santos   #
6   Department of Physiology and Biophysics, Federal University of Minas Gerais, Brazil
,
Rafaela F. da Silva   #
6   Department of Physiology and Biophysics, Federal University of Minas Gerais, Brazil
› Author Affiliations Financial support: This work was supported by the Brazilian Swiss Joint Research Program [590008/2010–2 to N.S, R.A.S.S., and F.M.]; Fundação de Amparo à Pesquisa do estado de Minas Gerais (FAPEMIG) [01/12 CBB APQ 01542/12 to R.F.S.]; Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ) [478065/2012–4 to R.F.S., 201603/2011–0 to R.A.FS.]; European Commission – Framework Programme for Research and Technological Development (EU FP7) [3201668 to F. Mach]; Swiss National Science Foundation Grants [#310030–118245 to F. Mach, #32002B-134963/1 to F. Montecucco]; Novartis Consumer Health [to R.A.FS] and Italian Ministry of Health [GR-2008–1135635 to A. Nencioni].
Further Information

Publication History

Received: 03 June 2013

Accepted after major revision: 11 February 2013

Publication Date:
29 November 2017 (online)

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Summary

Angiotensin (Ang)-(1–7), acting through the receptor Mas, has atheroprotective effects; however, its role on plaque vulnerability has been poorly studied. Here, we investigated the expression of the renin-angiotensin system (RAS) components in stable and unstable human carotid plaques. In addition, we evaluated the effects of the chronic treatment with an oral formulation of Ang-(1–7) in a mouse model of shear stress-determined carotid atherosclerotic plaque. Upstream and downstream regions of internal carotid plaques were obtained from a recently published cohort of patients asymptomatic or symptomatic for ischaemic stroke. Angiotensinogen and renin genes were strongly expressed in the entire cohort, indicating an intense intraplaque modulation of the RAS. Intraplaque expression of the Mas receptor mRNA was increased in the downstream portion of asymptomatic patients as compared to corresponding region in symptomatic patients. Conversely, AT1 receptor gene expression was not modified between asymptomatic and symptomatic patients. Treatment with Ang-(1–7) in ApoE-/- mice was associated with increased intraplaque collagen content in the aortic root and low shear stress-induced carotid plaques, and a decreased MMP-9 content and neutrophil and macrophage infiltration. These beneficial effects were not observed in the oscillatory shear stress-induced plaque. In vitro incubation with Ang-(1–7) did not affect ICAM-1 expression and apoptosis on cultured endothelial cells. In conclusion, Mas receptor is up regulated in the downstream portions of human stable carotid plaques as compared to unstable lesions. Treatment with the oral formulation of Ang-(1–7) enhances a more stable phenotype in atherosclerotic plaques, depending on the local pattern of shear stress forces.

Keywords

Angiotensin - atherosclerosis - inflammation - plaque stability

# These authors equally contributed as senior authors to this work.


 

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