Knockdown of Herp alleviates hyperhomocysteinemia mediated atherosclerosis through the inhibition of vascular smooth muscle cell phenotype switching

International Journal of Cardiology
Hui LinHangyuan Guo

Abstract

Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a key role in atherosclerosis. We aimed to investigate whether Homocysteine-responsive endoplasmic reticulum protein (Herp) was involved in VSMC phenotypic switching and affected atheroprogression. To assess the role of Herp in homocysteine (Hcy)-associated atherosclerosis, Herp-/- and LDLR-/- double knockout mice were generated and fed with a high methionine diet (HMD) to induce Hyperhomocysteinemia (HHcy). Atherosclerotic lesions, cholesterol homeostasis, endoplasmic reticulum (ER) stress activation, and the phenotype of VSMCs were assessed in vivo. We used siRNAs to knockdown Herp in cultured VSMCs to further validate our findings in vitro. HMD significantly activated the activating transcription factor 6 (ATF6)/Herp arm of ER stress in LDLR-/- mice, and induced the phenotypic switch of VSMCs, with the loss of contractile proteins (SMA and calponin) and an increase of OPN protein. Herp-/-/LDLR-/- mice developed reduced atherosclerotic lesions in the aortic sinus and the whole aorta when compared with LDLR-/- mice. However, Herp deficiency had no effect on diet-induced HHcy and hyperlipidemia. Inhibition of VSMC phenotypic switching, decreased proliferation an...Continue Reading

Citations

Aug 9, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Jia ShiFan He
Apr 28, 2019·Journal of Molecular Histology·Tingjuan NiHangyuan Guo
Sep 24, 2020·Oxidative Medicine and Cellular Longevity·Shengjie YangSongzi Wang
Feb 24, 2021·Nature Reviews. Cardiology·Jun RenYingmei Zhang
Jun 6, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Yanyan ZhangXiangchun Shen

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