Propranolol treatment lowers blood pressure, reduces vascular inflammatory markers and improves endothelial function in obese mice
Propranolol treatment lowers blood pressure, reduces vascular inflammatory markers and improves endothelial function in obese mice
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DOI：
10.1016/j.phrs.2017.05.018
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发表时间：
2017-08-01
影响因子：
9.3
通讯作者：
Davel, Ana P.
中科院分区：
文献类型：
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作者：
Franco, Nathalia da Silva;Lubaczeuski, Camila;Davel, Ana P.
肥胖相关高血压伴有许多心血管危险因素，包括血管胰岛素抵抗（IR）和较高的交感神经活动。因此，自主神经阻滞被证明可以逆转肥胖个体的高血压、内皮功能障碍和 IR。我们假设用普萘洛尔阻断 β-AR 可以恢复肥胖患者的内皮功能和血管胰岛素信号传导，并具有抗炎作用。对喂食标准饮食（对照组）或高脂饮食（HFD）的小鼠进行体重、收缩压（SBP）、血浆生化参数和主动脉内皮功能分析，并用载体（水）或普萘洛尔（10 mg/kg/天）治疗8周。普萘洛尔治疗并没有改变 HFD 喂养的致肥作用。然而，普萘洛尔可有效预防肥胖小鼠的收缩压升高、高胰岛素血症以及内皮依赖性乙酰胆碱和胰岛素松弛受损。普萘洛尔对内皮功能的保护作用与一氧化氮 (NO) 产生增加以及 Akt (Ser473) 和 eNOS (Ser1177) 磷酸化有关，但与磷酸化 IRS-1 (Ser307) 和磷酸化 ERK1/2 (Thr202/Tyr204) 减少有关。此外，β-受体阻滞剂普萘洛尔可防止肥胖小鼠主动脉中的 NF-κ B 核易位以及磷酸化 Iκ B-α (Ser32) 和白细胞介素 (IL)-6 表达的增加，而主动脉活性氧的产生或循环 IL-6 和 TNF-α 水平没有显着变化。在 β(2)-AR 敲除小鼠中，尽管体重和内脏脂肪增加，但 HFD 并未增加收缩压并显示出内皮功能的部分改善，揭示了 (β(2)-AR 在肥胖的心血管影响中的作用。总之，我们的结果表明，用普萘洛尔阻断 β-AR 可以有效预防 HFD 诱导的肥胖中显示的内皮功能障碍、血管 IR 和促炎症状态，与体重变化无关。(C) 2017 Elsevier Ltd. 保留所有权利。
Obesity-associated hypertension is accompanied by a number of cardiovascular risk factors including vascular insulin resistance (IR) and higher sympathetic nervous activity. Therefore, autonomic blockade was demonstrated to reverse hypertension, endothelial dysfunction and IR in obese individuals. We hypothesized that beta-AR blockade with propranolol would restore endothelial function and vascular insulin signaling in obesity, associated with an anti-inflammatory effect. Body weight, systolic blood pressure (SBP), plasma biochemical parameters and aortic endothelial function were analyzed in mice fed standard diet (control group) or a high fat diet (HFD) that were treated with vehicle (water) or propranolol (10 mg/kg/day) for 8 weeks. Propranolol treatment did not modify obesogenic effect of HFD feeding. However, propranolol was effective in preventing the rise in SBP, the hyperinsulinemia and the impaired endothelium-dependent relaxation to acetylcholine and to insulin in obese mice. Protective effect of propranolol administration in endothelial function was associated with increased nitric oxide (NO) production and phosphorylation of Akt (Ser473) and eNOS (Ser1177), but with reduced phosphoIRS-1(Ser307) and phospho-ERK1/2 (Thr202/Tyr204). In addition, (beta-blocker propranolol prevented the NF-kappa B nuclear translocation and the increase in phospho-I kappa B-alpha (Ser32) and in interleukin(IL)-6 expression in aorta of obese mice, without significant changes in either aortic reactive oxygen species production or in circulating IL-6 and TNF-alpha levels. In beta(2)-AR knockout mice, despite increasing body weight and visceral fat, HFD did not increase SBP and showed a partial improvement of endothelial function, revealing a role of (beta(2)-AR in cardiovascular effects of obesity. In conclusion, our results suggest that beta-AR blockade with propranolol is effective to prevent the endothelial dysfunction, vascular IR and pro-inflammatory state displayed in HFD-induced obesity, independent of changes in body weight. (C) 2017 Elsevier Ltd. All rights reserved.