title: Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice.
abstract: 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/6J mice. The mice were divided into 4 groups and treated with sham-operation (Sham, n=10), sham-operation and aliskiren (Sham+Aliskiren; 10mg/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.
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Arata
authors.initials: A
authors.lastname: Fukushima
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address: tuckahoe@med.hokudai.ac.jp.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kinugawa
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Takada
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Matsumoto
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Furihata
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Mizushima
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokota
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Shouji
authors.initials: S
authors.lastname: Matsushima
authors.affiliation: Graduate School of Lifelong Sport, Hokusho University, Ebetsu, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Okita
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D005650:Fumarates / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009203:Myocardial Infarction / Q000150:complications; D018384:Oxidative Stress / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D000093342:Prorenin Receptor; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D005650:Fumarates; D007328:Insulin; D011480:Protease Inhibitors; D011956:Receptors, Cell Surface; D000093342:Prorenin Receptor; D000092502:Renin Inhibitors; C446481:aliskiren
keywords: (Pro)renin receptor; Direct renin inhibitor; Heart failure; Insulin resistance; Oxidative stress; Skeletal muscle