title: Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents.
abstract: Although many animal studies indicate insulin has cardioprotective effects, clinical studies suggest a link between insulin resistance (hyperinsulinemia) and heart failure (HF). Here we have demonstrated that excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. Chronic pressure overload induced hepatic insulin resistance and plasma insulin level elevation. In contrast, cardiac insulin signaling was upregulated by chronic pressure overload because of mechanical stretch-induced activation of cardiomyocyte insulin receptors and upregulation of insulin receptor and Irs1 expression. Chronic pressure overload increased the mismatch between cardiomyocyte size and vascularity, thereby inducing myocardial hypoxia and cardiomyocyte death. Inhibition of hyperinsulinemia substantially improved pressure overload-induced cardiac dysfunction, improving myocardial hypoxia and decreasing cardiomyocyte death. Likewise, the cardiomyocyte-specific reduction of insulin receptor expression prevented cardiac ischemia and hypertrophy and attenuated systolic dysfunction due to pressure overload. Conversely, treatment of type 1 diabetic mice with insulin improved hyperglycemia during pressure overload, but increased myocardial ischemia and cardiomyocyte death, thereby inducing HF. Promoting angiogenesis restored the cardiac dysfunction induced by insulin treatment. We therefore suggest that the use of insulin to control hyperglycemia could be harmful in the setting of pressure overload and that modulation of insulin signaling is crucial for the treatment of HF.
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Ippei
authors.initials: I
authors.lastname: Shimizu
authors.forename: Tohru
authors.initials: T
authors.lastname: Minamino
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Toko
authors.forename: Sho
authors.initials: S
authors.lastname: Okada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ikeda
authors.forename: Noritaka
authors.initials: N
authors.lastname: Yasuda
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tateno
authors.forename: Junji
authors.initials: J
authors.lastname: Moriya
authors.forename: Masataka
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Aika
authors.initials: A
authors.lastname: Nojima
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akazawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shiojima
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000097:blood; D006333:Heart Failure; D000860:Hypoxia; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D011312:Pressure; D051381:Rats; D011918:Rats, Inbred SHR; D011972:Receptor, Insulin / Q000096:biosynthesis; D013314:Stress, Mechanical; D013599:Systole; D015854:Up-Regulation
chemical_list: D007328:Insulin; D011972:Receptor, Insulin
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