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)-γ 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-γ 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.