Angiotensin-(1-7) contributes to insulin-sensitizing effects of angiotensin-converting enzyme inhibition in obese mice
Angiotensin-(1-7) contributes to insulin-sensitizing effects of angiotensin-converting enzyme inhibition in obese mice
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DOI：
10.1152/ajpendo.00281.2018
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发表时间：
2018-12-01
影响因子：
5.1
通讯作者：
Arnold, Amy C.
中科院分区：
文献类型：
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作者：
Loloi, Justin;Miller, Amanda J.;Arnold, Amy C.
血管紧张素转换酶（ACE）抑制剂在心脏代谢综合征动物模型中可减轻体重、降低血压（BP）并改善胰岛素敏感性。这些作用通常归因于减少血管紧张素（Ang）II形成;然而，这些疗法也增加Ang-（1-7）的水平，这是一种对抗Ang II作用的有益激素。我们假设这种Ang-（1-7）的产生有助于肥胖小鼠中ACE抑制的胰岛素增敏作用。将成年雄性C57 BL/6 J小鼠置于60%高脂肪饮食中11周。在最后3周的饮食中，小鼠通过皮下渗透微型泵接受正常水或含有ACE抑制剂卡托普利（50 mg/l）以及Ang-（1-7）mas受体拮抗剂A779（400或800 ng.kg（-1）.min（-1））的水或盐水载体。在治疗结束时，测量动脉BP，并在接受载体、卡托普利、卡托普利加A779或A779的清醒肥胖小鼠中进行高胰岛素-正常血糖钳夹（n = 6-13/组）。在肥胖小鼠中，Captopril可减轻体重（28 +/- 2 vs. 41 +/- 2 g生理盐水; p = 0.001），降低收缩压（109 +/- 6 vs. 144 +/- 7 mmHg生理盐水; p=0.041），改善全身胰岛素敏感性（稳态葡萄糖输注速率：31 +/- 4 vs. 16 +/- 2 mg.kg（-1）.min生理盐水; p = 0.001）。A779减弱了卡托普利介导的胰岛素敏感性改善（23 +/- 2 mg.kg（-1）.min; p = 0.042），对体重（32 +/- 2 g; p = 0.441）或BP（111 +/- 7 mmHg; p = 0.788）无影响。A779单药对心脏代谢结局无影响。这些数据表明，ACE抑制的胰岛素增敏作用部分是由于Ang-（1-7）/mas受体途径的激活，并提供了新的见解，这些治疗的积极代谢作用的机制。
Angiotensin converting enzyme (ACE) inhibitors reduce body weight, lower blood pressure (BP), and improve insulin sensitivity in animal models of cardiometabolic syndrome. These effects are generally attributed to reduced angiotensin (Ang) II formation; however, these therapies also increase levels of Ang-(1-7), a beneficial hormone opposing Ang II actions. We hypothesized this Ang-(1-7) generation contributes to the insulin sensitizing effects of ACE inhibition in obese mice. Adult male C57BL/6J mice were placed on a 60% high fat diet for 11 weeks. During the last 3 weeks of diet, mice received normal water or water containing the ACE inhibitor captopril (50 mg/l) as well as the Ang-(1-7) mas receptor antagonist A779 (400 or 800 ng.kg(-1).min(-1)) or saline vehicle via subcutaneous osmotic mini-pumps. At the end of treatment, arterial BP was measured and hyperinsulinemic-euglycemic clamps were performed in conscious obese mice receiving vehicle, captopril, captopril plus A779, or A779 (n = 6-13/group). Captopril reduced body weight (28 +/- 2 vs. 41 +/- 2 g saline; p = 0.001), lowered systolic BP (109 +/- 6 vs.144 +/- 7 mmHg saline; p=0.041), and improved whole-body insulin sensitivity (steady-state glucose infusion rate: 31 +/- 4 vs. 16 +/- 2 mg.kg(-1).min saline; p = 0.001) in obese mice. A779 attenuated captopril-mediated improvements in insulin sensitivity (23 +/- 2 mg.kg(-1).min; p = 0.042), with no effect on body weight (32 +/- 2 g; p = 0.441) or BP (111 +/- 7 mmHg; p = 0.788). There was no effect of A779 alone on cardiometabolic outcomes. These data suggest that insulin-sensitizing effects of ACE inhibition are in part due to activation of Ang-(1-7)/mas receptor pathways, and provide new insight into mechanisms underlying the positive metabolic effects of these therapies.