1. Treatment with Angiotensin-(1-7) reduces inflammation in carotid atherosclerotic plaques
- Author
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Silvia Q Savergnini, Sébastien Lenglet, Fabrizio Montecucco, Franco Dallegri, Domenico Palombo, Giovanni Spinella, Nikolaos Stergiopulos, Debora Soncini, Frederico B. De Sousa, François Mach, Irene Caffa, Rodrigo A. Fraga-Silva, Graziano Pelli, Maria Bertolotto, Katia Galan, Rafaela F. da Silva, Alessio Nencioni, Robson A.S. Santos, Rubén D. Sinisterra, Bianca Pane, Aldo Pende, L. Capettini, and Fabiana P. Costa-Fraga
- Subjects
Pathology ,medicine.medical_specialty ,Anti-Inflammatory Agents/administration & dosage ,Anti-Inflammatory Agents ,Administration, Oral ,Inflammation ,030204 cardiovascular system & hematology ,ddc:616.07 ,Asymptomatic ,03 medical and health sciences ,Mice ,Angiotensin ,Apolipoproteins E ,0302 clinical medicine ,Downregulation and upregulation ,Peptide Fragments/administration & dosage/biosynthesis/genetics ,Renin–angiotensin system ,Gene expression ,medicine ,Animals ,Humans ,Inflammation/drug therapy/immunology ,Plaque, Atherosclerotic/drug therapy/immunology ,Receptor ,Atherosclerosis, Inflammation, Angiotensin, Plaque stability ,ddc:616 ,Mice, Knockout ,Angiotensin II receptor type 1 ,business.industry ,Carotid Arteries/drug effects/metabolism/pathology ,plaque stability ,Hematology ,Peptide Fragments ,Plaque, Atherosclerotic ,Mice, Inbred C57BL ,Disease Models, Animal ,Carotid Arteries ,Apoptosis ,inflammation ,Case-Control Studies ,Angiotensin I ,medicine.symptom ,atherosclerosis ,business ,Apolipoproteins E/genetics ,030217 neurology & neurosurgery ,Angiotensin I/administration & dosage/biosynthesis/genetics - Abstract
SummaryAngiotensin (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.