美托洛尔
内分泌学
内科学
过氧化物酶体增殖物激活受体
糖尿病性心肌病
辅活化剂
肉碱
肉碱O-棕榈酰转移酶
染色质免疫沉淀
心理压抑
阿尔法(金融)
受体
医学
转录因子
生物
基因表达
发起人
心力衰竭
β氧化
新陈代谢
生物化学
基因
心肌病
患者满意度
结构效度
护理部
作者
Vijay Sharma,Pavan Dhillon,Howard G. Parsons,Michael F. Allard,John H. McNeill
标识
DOI:10.1016/j.ejphar.2009.02.016
摘要
We have previously shown that metoprolol decreases carnitine palmitoyltransferase-1 (CPT-1) activity, a mechanism which may partly explain its beneficial effects in heart failure. It is possible that this effect occurs as a result of repression of cardiac CPT-1B expression. CPT-1B is induced by the transcription factors peroxisome proliferator activated receptor-alpha (PPAR-alpha) and PPAR-gamma-coactivator 1alpha (PGC1alpha) and repressed by upstream stimulatory factor-2 (USF-2). We therefore hypothesized that metoprolol represses CPT-1B by increasing USF-2-mediated repression of PGC1alpha. Male Wistar Rats were divided into 4 groups: control, control treated with metoprolol for 5 weeks, diabetic and diabetic treated with metoprolol for 5 weeks. After termination, the expression of CPT-1 isoforms, PPAR-alpha, PGC1alpha USF-1 and USF-2, as well as downstream targets were measured. Binding of PPAR-alpha, PGC1alpha and USF-2 to PGC1alpha was measured using coimmunoprecipitation. The occupation of PPAR-alpha and MEF-2A consensus sites in the CPT-1B promoter was measured using chromatin immunoprecipitation assays. Chronic metoprolol treatment decreased the expression of CPT-1B in diabetic hearts. The expression of USF-2 was increased by metoprolol in both control and diabetic hearts, but the association of USF-2 with PGC1alpha was increased by metoprolol only in diabetic hearts. Metoprolol prevented the increase in PGC1alpha occupation of the CPT-1B promoter region observed in the diabetic heart without affecting PPAR-alpha occupation. Metoprolol decreases CPT-1B expression by decreasing PGC1alpha-mediated coactivation of PPAR-alpha and MEF-2A. This is associated with increased PGC1alpha/ USF-2 binding, suggesting that USF-2 mediates the metoprolol-induced repression of PGC1alpha.
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