Suppressed Production of Soluble Fms-Like Tyrosine Kinase-1 Contributes to Myocardial Remodeling and Heart Failure.

Soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor, is involved in the pathogenesis of cardiovascular disease. However, the significance of sFlt-1 in heart failure has not been fully elucidated. We found that sFlt-1 is decreased in renal failure and serves as a key molecule in atherosclerosis. In this study, we aimed to investigate the role of the decreased sFlt-1 production in heart failure, using sFlt-1 knockout mice. sFlt-1 knockout mice and wild-type mice were subjected to transverse aortic constriction and evaluated after 7 days. The sFlt-1 knockout mice had significantly higher mortality (52% versus 15%; P=0.0002) attributable to heart failure and showed greater cardiac hypertrophy (heart weight to body weight ratio, 8.95±0.45 mg/g in sFlt-1 knockout mice versus 6.60±0.32 mg/g in wild-type mice; P<0.0001) and cardiac dysfunction, which was accompanied by a significant increase in macrophage infiltration and cardiac fibrosis, than wild-type mice after transverse aortic constriction. An anti–placental growth factor–neutralizing antibody prevented pressure overload–induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, monocyte chemoattractant protein-1 expression was significantly increased in the hypertrophied hearts of sFlt-1 knockout mice compared with wild-type mice. Monocyte chemoattractant protein-1 inhibition with neutralizing antibody ameliorated maladaptive cardiac remodeling in sFlt-1 knockout mice after transverse aortic constriction. In conclusion, decreased sFlt-1 production plays a key role in the aggravation of cardiac hypertrophy and heart failure through upregulation of monocyte chemoattractant protein-1 expression in pressure-overloaded heart.;博士(医学)・乙第1384号・平成28年11月24日;© 2016 American Heart Association, Inc.;The definitive version is available at " https://doi.org/10.1161/HYPERTENSIONAHA.116.07371 ";開始ページ : 678;終了ページ : 687;PubMed番号 : http://www.ncbi.nlm.nih.gov/pubmed/27480835

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書名 Suppressed Production of Soluble Fms-Like Tyrosine Kinase-1 Contributes to Myocardial Remodeling and Heart Failure.
著作者等 American Heart Association
Council for High Blood Pressure Research
Interamerican Society of Hypertension. Scientific Meeting
Kawakami Rika
Kawata Hiroyuki
Kumazawa Takuya
Matsui Masaru
Nakada Yasuki
Nakagawa Hitoshi
Nakano Tomoya
Nishida Taku
Okuda Aya
Okura Hiroyuki
Onoue Kenji
Saito Yoshihiko
Somekawa Satoshi
Takeda Yukiji
Uemura Shiro
Watanabe Makoto
Seno Ayako
書名別名 可溶性Flt-1産生低下は、心筋リモデリングおよび心不全増悪に寄与する
出版元 American Heart Association / Lippincott Williams & Wilkins
ページ数 v.
大きさ 28 cm
ISSN 0194911X
NCID AA00214236
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言語 英語
出版国 アメリカ合衆国
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