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Metoprolol reduces proinflammatory cytokines and atherosclerosis in ApoE-/- mice.

Ulleryd MA, Bernberg E, Yang LJ, Bergström GM, Johansson ME - Biomed Res Int (2014)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, P.O. Box 432, 405 30 Gothenburg, Sweden.

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.

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Metoprolol dose-finding (Study I). (a) 24-hour heart rate during baseline conditions after three different doses of metoprolol compared with Control mice. Metoprolol was administrated to C57BL76 mice via osmotic minipumps delivering 1.4 mg/kg per hour (dose 1, n = 4), 2.5 mg/kg per hour (dose 2, n = 4), or 4.1 mg/kg per hour (dose 3, n = 4). Average 24-hour values for each group are given in the figure; *P < 0.05, **P < 0.01 versus Control. (b) Heart rate increased for Control mice and metoprolol treated mice receiving dose 1 and dose 2 (1.4 mg/kg per hour and 2.5 mg/kg per hour, resp.) during air-jet stress compared to baseline. For mice receiving metoprolol dose 3 (4.1 mg/kg per hour) heart rate did not increase during air-jet stress, compared to baseline. *P < 0.05 versus baseline. Mice received metoprolol treatment for one week prior to heart rate measurements. Data are expressed as mean ± SEM.
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fig1: Metoprolol dose-finding (Study I). (a) 24-hour heart rate during baseline conditions after three different doses of metoprolol compared with Control mice. Metoprolol was administrated to C57BL76 mice via osmotic minipumps delivering 1.4 mg/kg per hour (dose 1, n = 4), 2.5 mg/kg per hour (dose 2, n = 4), or 4.1 mg/kg per hour (dose 3, n = 4). Average 24-hour values for each group are given in the figure; *P < 0.05, **P < 0.01 versus Control. (b) Heart rate increased for Control mice and metoprolol treated mice receiving dose 1 and dose 2 (1.4 mg/kg per hour and 2.5 mg/kg per hour, resp.) during air-jet stress compared to baseline. For mice receiving metoprolol dose 3 (4.1 mg/kg per hour) heart rate did not increase during air-jet stress, compared to baseline. *P < 0.05 versus baseline. Mice received metoprolol treatment for one week prior to heart rate measurements. Data are expressed as mean ± SEM.

Mentions: To find an appropriate dose of metoprolol for the atherosclerosis study we tested three different doses and their effects on heart rate. All three doses of metoprolol lowered resting heart rate during a 24-hour period. Although both doses 1 and 2 significantly reduced heart rate (Dunnett's, P < 0.05 and P < 0.01, resp.), the circadian rhythm was similar to the control situation. Dose 3, on the other hand, disrupted the circadian rhythm as well as markedly reducing heart rate (P < 0.01, Figure 1(a)). To further validate the metoprolol doses we performed air-jet stress. Air-jet stress markedly increased heart rate in control animals. Metoprolol doses 1 and 2 decreased the air-jet induced rise in heart rate; however, there was still a significant increase in heart rate. Only dose 3 abolished the heart rate response to air-jet stress (P < 0.05, Figure 1(b)). Hence, dose 2 was chosen for the following atherosclerosis study.


Metoprolol reduces proinflammatory cytokines and atherosclerosis in ApoE-/- mice.

Ulleryd MA, Bernberg E, Yang LJ, Bergström GM, Johansson ME - Biomed Res Int (2014)

Metoprolol dose-finding (Study I). (a) 24-hour heart rate during baseline conditions after three different doses of metoprolol compared with Control mice. Metoprolol was administrated to C57BL76 mice via osmotic minipumps delivering 1.4 mg/kg per hour (dose 1, n = 4), 2.5 mg/kg per hour (dose 2, n = 4), or 4.1 mg/kg per hour (dose 3, n = 4). Average 24-hour values for each group are given in the figure; *P < 0.05, **P < 0.01 versus Control. (b) Heart rate increased for Control mice and metoprolol treated mice receiving dose 1 and dose 2 (1.4 mg/kg per hour and 2.5 mg/kg per hour, resp.) during air-jet stress compared to baseline. For mice receiving metoprolol dose 3 (4.1 mg/kg per hour) heart rate did not increase during air-jet stress, compared to baseline. *P < 0.05 versus baseline. Mice received metoprolol treatment for one week prior to heart rate measurements. Data are expressed as mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109227&req=5

fig1: Metoprolol dose-finding (Study I). (a) 24-hour heart rate during baseline conditions after three different doses of metoprolol compared with Control mice. Metoprolol was administrated to C57BL76 mice via osmotic minipumps delivering 1.4 mg/kg per hour (dose 1, n = 4), 2.5 mg/kg per hour (dose 2, n = 4), or 4.1 mg/kg per hour (dose 3, n = 4). Average 24-hour values for each group are given in the figure; *P < 0.05, **P < 0.01 versus Control. (b) Heart rate increased for Control mice and metoprolol treated mice receiving dose 1 and dose 2 (1.4 mg/kg per hour and 2.5 mg/kg per hour, resp.) during air-jet stress compared to baseline. For mice receiving metoprolol dose 3 (4.1 mg/kg per hour) heart rate did not increase during air-jet stress, compared to baseline. *P < 0.05 versus baseline. Mice received metoprolol treatment for one week prior to heart rate measurements. Data are expressed as mean ± SEM.
Mentions: To find an appropriate dose of metoprolol for the atherosclerosis study we tested three different doses and their effects on heart rate. All three doses of metoprolol lowered resting heart rate during a 24-hour period. Although both doses 1 and 2 significantly reduced heart rate (Dunnett's, P < 0.05 and P < 0.01, resp.), the circadian rhythm was similar to the control situation. Dose 3, on the other hand, disrupted the circadian rhythm as well as markedly reducing heart rate (P < 0.01, Figure 1(a)). To further validate the metoprolol doses we performed air-jet stress. Air-jet stress markedly increased heart rate in control animals. Metoprolol doses 1 and 2 decreased the air-jet induced rise in heart rate; however, there was still a significant increase in heart rate. Only dose 3 abolished the heart rate response to air-jet stress (P < 0.05, Figure 1(b)). Hence, dose 2 was chosen for the following atherosclerosis study.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, P.O. Box 432, 405 30 Gothenburg, Sweden.

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.

Show MeSH
Related in: MedlinePlus