The ubiquitin ligase Nedd4 mediates oxidized low-density lipoprotein-induced downregulation of insulin-like growth factor-1 receptor.

American Journal of Physiology. Heart and Circulatory Physiology
Yusuke HigashiPatrice Delafontaine

Abstract

Oxidized low-density lipoprotein (LDL) is proatherogenic and induces smooth muscle cell apoptosis, which contributes to atherosclerotic plaque destabilization. We showed previously that oxidized LDL downregulates insulin-like growth factor-1 receptor in human smooth muscle cells and that this is critical for induction of apoptosis. To identify mechanisms, we exposed smooth muscle cells to 60 mug/ml oxidized LDL or native LDL and assessed insulin-like growth factor-1 receptor mRNA levels, protein synthesis rate, and receptor protein stability. Oxidized LDL decreased insulin-like growth factor-1 receptor mRNA levels by 30% at 8 h compared with native LDL, and this decrease was maintained for up to 20 h. However, insulin-like growth factor-1 receptor protein synthesis rate was not altered by oxidized LDL. Pulse-chase labeling experiments revealed that oxidized LDL reduced insulin-like growth factor-1 receptor protein half-life to 12.2+/-1.7 h from 24.4+/-4.7 h with native LDL. This destabilization of insulin-like growth factor-1 receptor protein was accompanied by enhanced receptor ubiquitination. Overexpression of dominant-negative Nedd4 prevented oxidized LDL-induced downregulation of insulin-like growth factor-1 receptor, sugge...Continue Reading

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Citations

Apr 17, 2015·Nature Communications·Toshiaki FukushimaShin-Ichiro Takahashi
Dec 29, 2016·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Ji-Hyun LeeJe-Yoel Cho
Aug 17, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Yusuke HigashiPatrice Delafontaine
Mar 31, 2012·Molecular Cancer Therapeutics·Giusy Di ConzaFabiola Moretti

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