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(Hypertension. 2004;44:277.)
© 2004 American Heart Association, Inc.

Scientific Contributions

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; 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.

Correspondence to Lucia Mazzolai, Service of Angiology, CHUV, University of Lausanne, 1011 Lausanne, Rue du Bugnon 46, Switzerland. E-mail lucia.mazzolai{at}chuv.hospvd.ch

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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