共 35 条
Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents
被引:181
作者:
Shimizu, Ippei
Minamino, Tohru
[2
]
Toko, Haruhiro
Okada, Sho
Ikeda, Hiroyuki
Yasuda, Noritaka
Tateno, Kaoru
Moriya, Junji
Yokoyama, Masataka
Nojima, Aika
Koh, Gou Young
[3
,4
]
Akazawa, Hiroshi
Shiojima, Ichiro
[5
]
Kahn, C. Ronald
[6
]
Abel, E. Dale
[7
,8
]
Komuro, Issei
[1
,5
]
机构:
[1] Chiba Univ, Dept Cardiovasc Sci & Med, Grad Sch Med, Chuo Ku, Chiba 2608670, Japan
[2] Japan Sci & Technol Agcy, PRESTO, Saitama, Japan
[3] Korea Adv Inst Sci & Technol, Taejon 305701, South Korea
[4] Biomed Res Ctr, Taejon, South Korea
[5] Osaka Univ, Sch Med, Dept Cardiovasc Med, Osaka, Japan
[6] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA
[7] Univ Utah, Sch Med, Program Mol Med, Salt Lake City, UT USA
[8] Univ Utah, Sch Med, Div Endocrinol Diabet & Metab, Salt Lake City, UT USA
关键词:
IDIOPATHIC DILATED CARDIOMYOPATHY;
MYOCARDIAL FATTY-ACID;
HEART-FAILURE;
GLUCOSE-METABOLISM;
TRANSGENIC MICE;
ANGIOTENSIN-II;
FAILING HEART;
HYPERTROPHY;
GROWTH;
RESISTANCE;
D O I:
10.1172/JCI40096
中图分类号:
R-3 [医学研究方法];
R3 [基础医学];
学科分类号:
1001 ;
摘要:
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.
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页码:1506 / 1514
页数:9
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