Lectin-like Oxidized Low-density Lipoprotein Receptor-1 (LOX-1) and Cardiac Fibroblast Growth

Wang, Xianwei; Khaidakov, Magomed; Ding, Zufeng; Mitra, Sona; Lu, Jianrong; Dai, Yong; Mehta, Jawahar L.

doi:10.1161/hypertensionaha.112.200659

Cited by 19 publications

(9 citation statements)

References 34 publications

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“…This agrees well with a reduced collagen deposition in atherosclerotic lesions of LOX-1 −/− mice (Hu et al, 2008a). Importantly, the pro-fibrotic activity of LOX-1 is not limited to atherosclerosis, but has also been observed in other disease models (Hu et al, 2009; Lu et al, 2012; Wang et al, 2012; Dai et al, 2014; Deng et al, 2016). It will be of interest if also in these contexts LOX-1 signaling is controlled by SPPL2a/b proteases.…”

Section: Discussionmentioning

confidence: 80%

Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis

Mentrup

Theodorou

Cabrera-Cabrera

et al. 2019

Journal of Experimental Medicine

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The lectin-like oxidized LDL receptor 1 (LOX-1) is a key player in the development of atherosclerosis. LOX-1 promotes endothelial activation and dysfunction by mediating uptake of oxidized LDL and inducing pro-atherogenic signaling. However, little is known about modulators of LOX-1–mediated responses. Here, we show that the function of LOX-1 is controlled proteolytically. Ectodomain shedding by the metalloprotease ADAM10 and lysosomal degradation generate membrane-bound N-terminal fragments (NTFs), which we identified as novel substrates of the intramembrane proteases signal peptide peptidase–like 2a and b (SPPL2a/b). SPPL2a/b control cellular LOX-1 NTF levels which, following self-association via their transmembrane domain, can activate MAP kinases in a ligand-independent manner. This leads to an up-regulation of several pro-atherogenic and pro-fibrotic targets including ICAM-1 and the connective tissue growth factor CTGF. Consequently, SPPL2a/b-deficient mice, which accumulate LOX-1 NTFs, develop larger and more advanced atherosclerotic plaques than controls. This identifies intramembrane proteolysis by SPPL2a/b as a novel atheroprotective mechanism via negative regulation of LOX-1 signaling.

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Section: Discussionmentioning

confidence: 80%

Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis

Mentrup

Theodorou

Cabrera-Cabrera

et al. 2019

Journal of Experimental Medicine

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“…It is generally acknowledged that LOX-1 is a critical player in atherogenesis (6,7). Recent studies have implicated LOX-1 in cardiac remodeling following myocardial infarction and in models of hypertension (8)(9)(10). Blockade or deletion of LOX-1 has been shown to attenuate myocardial fibrosis in the rodent models (9,10).…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies have implicated LOX-1 in cardiac remodeling following myocardial infarction and in models of hypertension (8)(9)(10). Blockade or deletion of LOX-1 has been shown to attenuate myocardial fibrosis in the rodent models (9,10). However, whether LOX-1 also affects cardiac fibrosis related to aging still remains unknown.…”

Section: Introductionmentioning

confidence: 99%

LOX-1 Deletion Attenuates Myocardial Fibrosis in the Aged Mice, Particularly Those With Hypertension

Tang

Liu

et al. 2021

Front. Cardiovasc. Med.

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Background: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a transmembrane glycoprotein that mediates uptake of oxidized low-density lipoprotein (ox-LDL) into cells. Previous studies had shown that LOX-1 deletion had a potential to inhibit cardiac fibrosis in mouse models of hypertension and myocardial infarction. Whether LOX-1 deletion also affects cardiac fibrosis associated with aging still remains unknown. The aim of this study was to investigate the effect of LOX-1 deletion on myocardial fibrosis in the aged mice.Methods: C57BL/6 mice and LOX-1 knockout (KO) mice with C57BL/6 background were studied to the age of 60 weeks. Both genotypes of aged mice were exposed to angiotensin II (Ang II) or saline for additional 4 weeks. The mice were then sacrificed, and myocardial fibrosis, reactive oxygen species (ROS) and expression of LOX-1, fibronectin, collagens, p22phox, and gp91phox were measured.Results: LOX-1 deletion markedly reduced Ang II-mediated rise of blood pressure in the aged mice (vs. saline-treated mice). LOX-1 deletion also limited fibrosis and decreased fibronectin and collagen-3 expression in the hearts of aged mice, but not the expression of collagen-1 and collagen-4. LOX-1 deletion also inhibited ROS production and p22phox expression. As the aged mice were exposed to Ang II for 4 weeks (resulting in hypertension), LOX-1 deletion more pronounced inhibiting myocardial fibrosis and ROS production, and decreasing expression of fibronectin, collagen-1, collagen-2, collagen-3, p22phox, and gp91phox.Conclusion: LOX-1 deletion limited fibrosis and ROS production in the hearts of aged mice. This effect was more pronounced in the aged mice with hypertension induced by Ang II infusion.

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“…GPR4 signaling regulates endothelial cell adhesion through the cAMP pathway. It is known that the oxidized low density lipoprotein receptor 1 ( Olr1 ) regulates growth of a variety of cells and is important in inflammation, oxidative stress, and tissue remodeling (36). However, the expression and regulation of Olr1 remain unclear in the uterus.…”

Section: Discussionmentioning

confidence: 99%

Profiling of circadian genes expressed in the uterus endometrial stromal cells of pregnant rats as revealed by DNA microarray coupled with RNA interference

et al. 2013

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The peripheral circadian oscillator plays an essential role in synchronizing local physiology to operate in a circadian manner via regulation of the expression of clock-controlled genes. The present study aimed to evaluate the circadian rhythms of clock genes and clock-controlled genes expressed in the rat uterus endometrial stromal cells (UESCs) during the stage of implantation by a DNA microarray. Of 12,252 genes showing significantly expression, 7,235 genes displayed significant alterations. As revealed by the biological pathway analysis using the database for annotation, visualization, and integrated discovery online annotation software, genes were involved in cell cycle, glutathione metabolism, MAPK signaling pathway, fatty acid metabolism, ubiquitin mediated proteolysis, focal adhesion, and PPAR signaling pathway. The clustering of clock genes were mainly divided into four groups: the first group was Rorα, Timeless, Npas2, Bmal1, Id2, and Cry2; the second group Per1, Per2, Per3, Dec1, Tef, and Dbp; the third group Bmal2, Cry1, E4bp4, Rorβ, and Clock; the fourth group Rev-erbα. Eleven implantation-related genes and 24 placenta formation-related genes displayed significant alterations, suggesting that these genes involved in implantation and placenta formation are controlled under circadian clock. Some candidates as clock-controlled genes were evaluated by using RNA interference to Bmal1 mRNA. Down-regulation of Igf1 gene expression was observed by Bmal1 silencing, whereas the expression of Inhβa was significantly increased. During active oscillation of circadian clock, the apoptosis-related genes Fas and Caspase3 remained no significant changes, but they were significantly increased by knockdown of Bmal1 mRNA. These results indicate that clock-controlled genes are up- or down-regulated in rat UESCs during the stage of decidualization. DNA microarray analysis coupled with RNA interference will be helpful to understand the physiological roles of some oscillating genes in blastocyst implantation and placenta formation.

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Lectin-like Oxidized Low-density Lipoprotein Receptor-1 (LOX-1) and Cardiac Fibroblast Growth

Cited by 19 publications

References 34 publications

Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis

Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis

LOX-1 Deletion Attenuates Myocardial Fibrosis in the Aged Mice, Particularly Those With Hypertension

Profiling of circadian genes expressed in the uterus endometrial stromal cells of pregnant rats as revealed by DNA microarray coupled with RNA interference

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