Effect of metoprolol on vulnerable plaque in rabbits by changing shear stress around plaque and reducing inflammation.
ABSTRACT The beta-adrenoceptor antagonists are known to reduce cardiovascular events, but less is known about their effects on vulnerable plaque. The purpose of this study is to explore the role of metoprolol on vulnerable plaque and the possible mechanism. Vulnerable plaque model was established by local transfection with p53 gene in New Zealand Rabbits. Metoprolol treatment attenuated vessel positive remodeling and reduced vulnerability index (1.61+/-0.58 vs. 2.33+/-0.12, P<0.01). Although the difference did not reach statistical significance, the rate of rupture of atherosclerotic plaque (31% vs. 75%) and intima-media thickness (0.05+/-0.01 vs. 0.08+/-0.01 cm) were less in the metoprolol group than in the control group. The level of shear stress-related inflammatory cytokines such as intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), matrix metalloproteinase 1 (MMP-1), were lower in the metoprolol group than in the control group (P<0.01). Compared with control group, total cholesterol and low-density lipoprotein cholesterol were lower (P<0.01) in the metoprolol group. After metoprolol treatment, shear stress increased, and was not different to baseline (physiological shear stress, P>0.05). Shear stress and vulnerability index showed a negative correlation. These findings suggest that metoprolol could inhibit the development of atherosclerosis and stabilize vulnerable plaque by regulation of lipid and reduction of inflammation, in which the change from low shear stress to physiological shear stress around plaque may play an important role.
SourceAvailable from: Maria E Johansson[Show abstract] [Hide abstract]
ABSTRACT: A few studies in animals and humans suggest that metoprolol (β1-selective adrenoceptor antagonist) may have a direct antiatherosclerotic effect. However, the mechanism behind this protective effect has not been established. The aim of the present study was to evaluate the effect of metoprolol on development of atherosclerosis in ApoE(-/-) mice and investigate its effect on the release of proinflammatory cytokines. Male ApoE(-/-) mice were treated with metoprolol (2.5 mg/kg/h) or saline for 11 weeks via osmotic minipumps. Atherosclerosis was assessed in thoracic aorta and aortic root. Total cholesterol levels and Th1/Th2 cytokines were analyzed in serum and macrophage content in lesions by immunohistochemistry. Metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta (P < 0.05 versus Control). Further, metoprolol reduced serum TNFα and the chemokine CXCL1 (P < 0.01 versus Control for both) as well as decreasing the macrophage content in the plaques (P < 0.01 versus Control). Total cholesterol levels were not affected. In this study we found that a moderate dose of metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta of ApoE(-/-) mice. Metoprolol also decreased serum levels of proinflammatory cytokines TNFα and CXCL1 and macrophage content in the plaques, showing that metoprolol has an anti-inflammatory effect.06/2011; 12(1):71-71. DOI:10.1016/S1567-5688(11)70329-4
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ABSTRACT: It has been shown that oxidative stress may play an important role in the development of atherosclerosis, and carvedilol has the capacity of reducing oxidative stress. Accordingly, we assessed the hypothesis that carvedilol may reduce the severity of atherosclerosis in apolipoprotein E (apoE)-deficient mice in addition to its hemodynamic effects. Atherosclerosis was induced in apoE-deficient mice fed a high-fat diet containing 0.3% cholesterol. Mice were orally treated with propranolol (30 mg/kg/day), metoprolol (75 mg/kg/day) and carvedilol (10 mg/kg/day) over eight weeks (each group n = 7-9). Fatty streak plaque developed in apoE-deficient mice, and was suppressed in mice treated with all three drugs. The accumulation of macrophages and expression of CD4(+) and CD8(+) cells in the lesions were decreased by the treatment of the drugs, of which carvedilol was the most effective. In addition, carvedilol reduced superoxide production in aortic walls detected by ethidium staining. There were no significant changes in blood pressure among the study groups. The heart rates in the treated groups were decreased by 4%-12% compared with the control group, with carvedilol yielding the highest suppression of heart rate. The β-blocker treatment did not significantly modify the serum lipid profiles. Carvedilol may suppress atherosclerosis via reducing superoxide production, in addition to the hemodynamic modifications in this animal model.Experimental Biology and Medicine 09/2012; 237(9):1039-44. DOI:10.1258/ebm.2012.012022 · 2.23 Impact Factor
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ABSTRACT: Objectives: Systemic or local inflammation causes cardiac nerve sprouting and consequent arrhythmia. Metoprolol can prevent sympathetic nerve remodeling after myocardial infarction (MI), but the underlying mechanism is unclear. In this study, we evaluated the role of metoprolol in ameliorating sympathetic sprouting. Methods: Rabbits underwent ligation of the coronary artery for MI. MI rabbits received metoprolol or saline for 7 days. Immunohistochemistry was used to measure cardiac nerve sprouting and sympathetic innervations. Nuclear factor-κB (NF-κB) DNA binding activity was analyzed by electrophoretic mobility shift assay. The protein levels of NF-κB p65, inhibitor κBα (IκBα) and nerve growth factor (NGF) were detected by Western blot analysis. The mRNA levels of NGF, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were examined by quantitative real-time PCR. Results: MI rabbits showed nerve sprouting and sympathetic hyperinnervation. In MI rabbits, as compared with saline treatment, metoprolol reduced NF-κB DNA binding activity and NF-κB p65 level, and increased IκBα level. Moreover, metoprolol downregulated IL-1β, TNF-α and NGF levels, and reduced the density of sympathetic nerve fibers. Conclusions: Metoprolol ameliorates sympathetic nerve sprouting in rabbits after MI and is associated in part with inhibiting NF-κB activity.Cardiology 07/2013; 126(1):50-58. DOI:10.1159/000351074 · 2.04 Impact Factor