Key result
Endogenously increased angiotensin II in hypertensive ApoE-/- mice induced vulnerable plaques with thinner fibrous caps, larger lipid cores, and increased macrophage content (all P<0.01).
Why the study?
Does endogenously increased angiotensin II induce atherosclerotic plaque vulnerability in hypertensive hypercholesterolemic ApoE-/- mice?
Does endogenously increased angiotensin II induce atherosclerotic plaque vulnerability in hypertensive hypercholesterolemic ApoE-/- mice?
p-value: p=<0.01
Angiotensin II independently promotes atherosclerotic plaque vulnerability and elicits a Th1 response in a mouse model of hypertension and hypercholesterolemia.
No immediate clinical implications for plaque stabilization; leaves open translation of angiotensin II effects to human atherosclerosis.
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.
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Mazzolai et al. (2004) studied Atherosclerotic plaque vulnerability. Endogenously increased angiotensin II production vs. Normal angiotensin II production was evaluated on Plaque vulnerability (fibrous cap thickness, lipid core size, macrophage content) (p=<0.01). Endogenously increased angiotensin II in hypertensive ApoE-/- mice induced vulnerable plaques with thinner fibrous caps, larger lipid cores, and increased macrophage content (all P<0.01).