Published Online
on August 9, 2004

A more recent version of this article appeared on September 1, 2004

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Submitted on May 7, 2004
Revised on May 20, 2004

Endogenous Angiotensin II Induces Atherosclerotic Plaque Vulnerability and Elicits a Th1 Response in ApoE^-/- Mice

Lucia Mazzolai^*; Michel A. Duchosal; Martine Korber; Karima Bouzourene; Jean François Aubert; Hiroyuki Hao; Veronique Vallet; Hans-R. Brunner; Jürg Nussberger; Giulio Gabbiani; and Daniel Hayoz

From the Service of Angiology (L.M., M.K., K.B., J.F.A., H.R.B., J.N., D.H.) and the Service of Hematology (M.A.D, V.V.), CHUV, University of Lausanne, Switzerland; Department of Pathology (H.H., G.G.), University of Geneva, Switzerland. H.H. is currently affiliated with the Department of Pathology, National Cardiovascular Center, Osaka, Fujishirodai, Japan.

^* To whom correspondence should be addressed. E-mail: lucia.mazzolai{at}chuv.hospvd.ch.

Abstract--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)- 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- 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.

Key words: angiotensin • atherosclerosis • lymphocytes • interferon

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