Treatment with Angiotensin-(1-7) reduces inflammation in carotid atherosclerotic plaques.
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.
Rodrigo A
RA
Fraga-Silva
Silvia Q
SQ
Savergnini
Fabrizio
F
Montecucco
Alessio
A
Nencioni
Irene
I
Caffa
Debora
D
Soncini
Fabiana P
FP
Costa-Fraga
Frederico B
FB
De Sousa
Ruben D
RD
Sinisterra
Luciano A S
LA
Capettini
Sébastien
S
Lenglet
Katia
K
Galan
Graziano
G
Pelli
Maria
M
Bertolotto
Aldo
A
Pende
Giovanni
G
Spinella
Bianca
B
Pane
Franco
F
Dallegri
Domenico
D
Palombo
François
F
Mach
Nikolaos
N
Stergiopulos
Robson Augusto Souza dos Santos, Departamento de Fisiologia e Biofísica, Federal University of Minas Gerais, Av. Antonio Carlos, 6627 - UFMG, 31270-901 - Belo Horizonte, MG, Brazil, Tel.: +55 31 3409 2956, E-mail: robsonsant@gmail.com.
Robson A S
RA
Santos
Rafaela Fernandes da Silva, Departamento de Fisiologia e Biofísica, Federal University of Minas Gerais, Av. Antonio Carlos, 6627 - UFMG, 31270-901 - Belo Horizonte, MG, Brazil, Tel.: +55 31 3409 2956, E-mail: rfdasilva@icb.ufmg.br.
Rafaela F
RF
da Silva
D000284:Administration, Oral; D000803:Angiotensin I / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001057:Apolipoproteins E / Q000235:genetics; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000276:immunology
D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D010446:Peptide Fragments; D000803:Angiotensin I; C118790:angiotensin I (1-7)
Angiotensin; atherosclerosis; inflammation; plaque stability