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 Ϫ/Ϫ mice with either normal or endogenously increased angiotensin II production (renovascular hypertension models). Hypertensive high angiotensin II ApoE Ϫ/Ϫ mice developed unstable plaques, whereas in hypertensive normal angiotensin II ApoE Ϫ/Ϫ mice plaques showed a stable phenotype. Vulnerable plaques from high angiotensin II ApoE Ϫ/Ϫ mice had thinner fibrous cap (PϽ0.01), larger lipid core (PϽ0.01), and increased macrophage content (PϽ0.01) than even more hypertensive but normal angiotensin II ApoE Ϫ/Ϫ mice. Moreover, in mice with high angiotensin II, a skewed T helper type 1-like phenotype was observed. Splenocytes from high angiotensin II ApoE Ϫ/Ϫ mice produced significantly higher amounts of interferon (IFN)-␥ than those from ApoE Ϫ/Ϫ 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.

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