Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice

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• 作者：Arata Fukushima^a ; Shintaro Kinugawa^a ; ^{tuckahoe@med.hokudai.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Shingo Takada^a ; Junichi Matsumoto^a ; Takaaki Furihata^a ; Wataru Mizushima^a ; Masaya Tsuda^a ; Takashi Yokota^a ; Shouji Matsushima^a ; Koichi Okita^b ; Hiroyuki Tsutsui^a
• 关键词：Direct renin inhibitor ; Insulin resistance ; Heart failure ; Skeletal muscle ; Oxidative stress ; (Pro)renin receptor
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 May 2016
• 年：2016
• 卷：779
• 期：Complete
• 页码：147-156
• 全文大小：3351 K

文摘

Insulin resistance can occur as a consequence of heart failure (HF). Activation of the renin-angiotensin system (RAS) may play a crucial role in this phenomenon. We thus investigated the effect of a direct renin inhibitor, aliskiren, on insulin resistance in HF after myocardial infarction (MI). MI and sham operation were performed in male C57BL/6 J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10 mg/kg/day, n=10), MI (n=11), or MI and aliskiren (MI+Aliskiren, n=11). After 4 weeks, MI mice showed left ventricular dilation and dysfunction, which were not affected by aliskiren. The percent decrease of blood glucose after insulin load was significantly smaller in MI than in Sham (14±5% vs. 36±2%), and was ameliorated in MI+Aliskiren (34±5%) mice. Insulin-stimulated serine-phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle of MI compared to Sham by 57% and 69%, and both changes were ameliorated in the MI+Aliskiren group (91% and 94%). Aliskiren administration in MI mice significantly inhibited plasma renin activity and angiotensin II (Ang II) levels. Moreover, (pro)renin receptor expression and local Ang II production were upregulated in skeletal muscle from MI and were attenuated in MI+Aliskiren mice, in tandem with a decrease in superoxide production and NAD(P)H oxidase activities. In conclusion, aliskiren ameliorated insulin resistance in HF by improving insulin signaling in the skeletal muscle, at least partly by inhibiting systemic and (pro)renin receptor-mediated local RAS activation, and subsequent NAD(P)H oxidase-induced oxidative stress.