Endogenous angiotensin II induces atherosclerotic plaque vulnerability and elicits a Th1 response in ApoE-/- mice.
Rupture of vulnerable plaques is the main cause of acute cardiovascular events. However, mechanisms responsible for transforming a stable into a vulnerable plaque remain elusive. Angiotensin II, a key regulator of blood pressure homeostasis, has a potential role in atherosclerosis. To study the contribution of angiotensin II in plaque vulnerability, we generated hypertensive hypercholesterolemic ApoE-/- mice with either normal or endogenously increased angiotensin II production (renovascular hypertension models). Hypertensive high angiotensin II ApoE-/- mice developed unstable plaques, whereas in hypertensive normal angiotensin II ApoE-/- mice plaques showed a stable phenotype. Vulnerable plaques from high angiotensin II ApoE-/- mice had thinner fibrous cap (P<0.01), larger lipid core (P<0.01), and increased macrophage content (P<0.01) than even more hypertensive but normal angiotensin II ApoE-/- mice. Moreover, in mice with high angiotensin II, a skewed T helper type 1-like phenotype was observed. Splenocytes from high angiotensin II ApoE-/- mice produced significantly higher amounts of interferon (IFN)-gamma than those from ApoE-/- mice with normal angiotensin II; secretion of IL4 and IL10 was not different. In addition, we provide evidence for a direct stimulating effect of angiotensin II on lymphocyte IFN-gamma production. These findings suggest a new mechanism in plaque vulnerability demonstrating that angiotensin II, within the context of hypertension and hypercholesterolemia, independently from its hemodynamic effect behaves as a local modulator promoting the induction of vulnerable plaques probably via a T helper switch.
Service of Angiology, CHUV, University of Lausanne, 1011 Lausanne, Rue du Bugnon 46, Switzerland. lucia.mazzolai@chuv.hospvd.ch
Lucia
L
Mazzolai
Michel A
MA
Duchosal
Martine
M
Korber
Karima
K
Bouzourene
Jean François
JF
Aubert
Hiroyuki
H
Hao
Veronique
V
Vallet
Hans-R
HR
Brunner
Jürg
J
Nussberger
Giulio
G
Gabbiani
Daniel
D
Hayoz
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D001161:Arteriosclerosis / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D003324:Coronary Artery Disease / Q000209:etiology / Q000276:immunology / Q000473:pathology; D005355:Fibrosis; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D006978:Hypertension, Renovascular / Q000276:immunology / Q000503:physiopathology*; D008026:Ligation; D051379:Mice; D018345:Mice, Knockout; D009392:Nephrectomy; D012077:Renal Artery; D012083:Renin / Q000097:blood*; D012084:Renin-Angiotensin System / Q000502:physiology*; D012422:Rupture, Spontaneous; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D014657:Vasculitis / Q000150:complications* / Q000276:immunology
D001057:Apolipoproteins E; D000804:Angiotensin II; D012083:Renin