(Pro)renin receptor in skeletal muscle is involved in the development of insulin resistance associated with postinfarct heart failure in mice
(Pro)renin receptor in skeletal muscle is involved in the development of insulin resistance associated with postinfarct heart failure in mice
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DOI：
10.1152/ajpendo.00449.2013
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发表时间：
2014-09-15
影响因子：
5.1
通讯作者：
Tsutsui, Hiroyuki
中科院分区：
文献类型：
--
作者：
Fukushima, Arata;Kinugawa, Shintaro;Tsutsui, Hiroyuki
我们先前报道了胰岛素抵抗是由心力衰竭（HF）通过NAD（P）H氧化酶依赖的氧化应激损伤骨骼肌中的胰岛素信号转导引起的。(Pro)肾素受体[（P）RR]参与局部肾素-血管紧张素系统的激活和随后的氧化应激。因此，我们研究了（P）RR抑制剂、柄区肽（HRP）是否可以通过改善骨骼肌中的氧化应激和胰岛素信号传导来改善心肌梗死（MI）后HF的胰岛素抵抗。将C57 BL 6 J小鼠分为四组：假手术组（Sham，n = 10）、用HRP处理的假手术组（Sham + HRP，0.1 mg.kg（-1）.day（-1），n = 10）、MI手术组（MI，n = 10）和用HRP处理的MI组（MI + HRP，0.1 mg/kg/天，n = 10）。心肌梗死4周后，心肌梗死小鼠出现左心室功能不全，而HRP对左心室功能无影响。(P)心肌梗死后骨骼肌RR显著升高（149%，P < 0.05）。胰岛素负荷后，MI组血糖下降幅度小于假手术组（21 +/- 2 vs. 44 +/-3%，P < 0.05），MI + HRP组血糖下降幅度大于MI组（38 +/-2%，P < 0.05）。胰岛素刺激的Akt丝氨酸磷酸化和葡萄糖转运蛋白4易位在MI的骨骼肌中分别减少了48%和49%的Sham，这两个都在MI + HRP中得到改善。MI组超氧化物歧化酶（SOD）和NAD（P）H氧化酶活性增加，而MI + HRP组SOD和NAD（P）H氧化酶活性降低。HRP通过抑制骨骼肌中NAD（P）H氧化酶诱导的超氧化物产生，改善胰岛素信号传导，从而改善HF相关的胰岛素抵抗。（P）RR通路参与胰岛素抵抗的发展，至少部分是通过HF导致骨骼肌中胰岛素信号传导受损。
We previously reported that insulin resistance was induced by the impairment of insulin signaling in the skeletal muscle from heart failure (HF) via NAD(P) H oxidase-dependent oxidative stress. (Pro) renin receptor [(P)RR] is involved in the activation of local renin-angiotensin system and subsequent oxidative stress. We thus examined whether (P) RR inhibitor, handle region peptide (HRP), could ameliorate insulin resistance in HF after myocardial infarction (MI) by improving oxidative stress and insulin signaling in the skeletal muscle. C57BL6J mice were divided into four groups: sham operated (Sham, n = 10), Sham treated with HRP (Sham + HRP, 0.1 mg.kg(-1).day(-1), n = 10), MI operated (MI, n = 10), and MI treated with HRP (MI + HRP, 0.1 mg/kg/day, n = 10). After 4 wk, MI mice showed left ventricular dysfunction, which was not affected by HRP. (P) RR was upregulated in the skeletal muscle after MI (149% of sham, P < 0.05). The decrease in plasma glucose after insulin load was smaller in MI than in Sham (21 +/- 2 vs. 44 +/- 3%, P < 0.05), and was greater in MI + HRP (38 +/- 2%, P < 0.05) than in MI. Insulin-stimulated serine phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle from MI by 48 and 49% of Sham, both of which were ameliorated in MI + HRP. Superoxide production and NAD(P) H oxidase activities were increased in MI, which was inhibited in MI + HRP. HRP ameliorated insulin resistance associated with HF by improving insulin signaling via the inhibition of NAD(P) H oxidase-induced superoxide production in the skeletal muscle. The (P) RR pathway is involved in the development of insulin resistance, at least in part, via the impairment of insulin signaling in the skeletal muscle from HF.