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

Rodrigo A. Fraga-Silva; Silvia Q. Savergnini; Fabrizio Montecucco; Alessio Nencioni; Irene Caffa; Debora Soncini; Fabiana P. Costa-Fraga; Frederico B. De Sousa; Ruben D. Sinisterra; Luciano A. S. Capettini; Sébastien Lenglet; Katia Galan; Graziano Pelli; Maria Bertolotto; Aldo Pende; Giovanni Spinella; Bianca Pane; Franco Dallegri; Domenico Palombo; François Mach; Nikolaos Stergiopulos; Robson A. S. Santos; Rafaela F. da Silva

doi:10.1160/TH13-06-0448

Thrombosis and Haemostasis, Inhaltsverzeichnis

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

¹Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

,

Silvia Q. Savergnini

¹Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

,

Fabrizio Montecucco

²Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland

³First 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

³First 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

³First 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

³First 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

¹Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

,

Frederico B. De Sousa

⁴Department of Chemistry, Federal University of Minas Gerais, Brazil

,

Ruben D. Sinisterra

⁴Department of Chemistry, Federal University of Minas Gerais, Brazil

,

Luciano A. S. Capettini

¹Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

,

Sébastien Lenglet

²Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland

,

Katia Galan

²Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland

,

Graziano Pelli

²Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland

,

Maria Bertolotto

³First 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

³First 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

⁵Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy

,

Bianca Pane

⁵Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy

,

Franco Dallegri

³First 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

⁵Vascular and Endovascular Surgery Unit, Department of Surgery, San Martino Hospital, Genoa, Italy

,

François Mach

²Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland

,

Nikolaos Stergiopulos

¹Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

,

Robson A. S. Santos^#

⁶Department of Physiology and Biophysics, Federal University of Minas Gerais, Brazil

,

Rafaela F. da Silva^#

⁶Department of Physiology and Biophysics, Federal University of Minas Gerais, Brazil

› Institutsangaben

Abstract

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

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Referenzen

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