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

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiao Li ◽  
Xihe Tang ◽  
Bo Liu ◽  
Jinghang Zhang ◽  
Yongxi Zhang ◽  
...  

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.

2013 ◽  
Vol 305 (2) ◽  
pp. H155-H162 ◽  
Author(s):  
Sayoko Ogura ◽  
Tatsuo Shimosawa ◽  
ShengYu Mu ◽  
Takashi Sonobe ◽  
Fumiko Kawakami-Mori ◽  
...  

Chronic hypoxia is one of the main causes of pulmonary hypertension (PH) associated with ROS production. Lectin-like oxidized low-density lipoprotein receptor (LOX)-1 is known to be an endothelial receptor of oxidized low-density lipoprotein, which is assumed to play a role in the initiation of ROS generation. We investigated the role of LOX-1 and ROS generation in PH and vascular remodeling in LOX-1 transgenic (TG) mice. We maintained 8- to 10-wk-old male LOX-1 TG mice and wild-type (WT) mice in normoxia (room air) or hypoxia (10% O2 chambers) for 3 wk. Right ventricular (RV) systolic pressure (RVSP) was comparable between the two groups under normoxic conditions; however, chronic hypoxia significantly increased RVSP and RV hypertrophy in LOX-1 TG mice compared with WT mice. Medial wall thickness of the pulmonary arteries was significantly greater in LOX-1 TG mice than in WT mice. Furthermore, hypoxia enhanced ROS production and nitrotyrosine expression in LOX-1 TG mice, supporting the observed pathological changes. Administration of the NADPH oxidase inhibitor apocynin caused a significant reduction in PH and vascular remodeling in LOX-1 TG mice. Our results suggest that LOX-1-ROS generation induces the development and progression of PH.


2018 ◽  
Vol 132 (21) ◽  
pp. 2369-2381 ◽  
Author(s):  
Floor Spaans ◽  
Anita Quon ◽  
Stewart R. Rowe ◽  
Jude S. Morton ◽  
Raven Kirschenman ◽  
...  

Syncytiotrophoblast extracellular vesicles (STBEVs), released into the maternal circulation during pregnancy, have been shown to affect vascular function; however, the mechanism remains unknown. In rats, STBEVs were shown to reduce endothelium-mediated vasodilation via lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a multi-ligand scavenger receptor that has been associated with vascular dysfunction. Recently, LOX-1 was shown to interact with the angiotensin II type 1 receptor (AT-1). We hypothesized that, in pregnant mice, STBEVs would impair vascular function via LOX-1 and would specifically affect angiotensin II responses. Uterine arteries from pregnant control (C57BL/6) and LOX-1 knockout (LOX-1KO) mice were isolated on gestational day (GD) 18.5. Endothelium-dependent (methylcholine (MCh); ± N(G)-Nitro-L-arginine methyl ester to assess nitric oxide (NO) contribution), and -independent (sodium nitroprusside) vasodilation, and vasoconstriction (angiotensin II; ± AT-1 [candesartan] or angiotensin II type 2 receptor (AT-2) [PD123.319] receptor antagonists; high potassium salt solution) responses were assessed using wire myography. AT-1 and AT-2 expression was analyzed using fluorescence microscopy. Human umbilical vein endothelial cells (HUVECs) were stimulated with STBEVs ± LOX-1 blocking antibody, and superoxide and peroxynitrite production were analyzed. Although MCh-induced vasodilation was decreased (P=0.0012), NO contribution to vasodilation was greater in LOX-1KO mice (P=0.0055). STBEVs delayed angiotensin II tachyphylaxis in arteries from control but not LOX-1KO mice (P<0.0001), while AT-1 and AT-2 expression was unchanged. STBEVs increased peroxynitrite production in HUVECs via LOX-1 (P=0.0091). In summary, LOX-1 deletion altered endothelium-mediated vasodilation, suggesting that LOX-1 contributes to vascular adaptations in pregnancy. STBEVs increased angiotensin II responsiveness and oxidative stress levels via LOX-1, suggesting that increased LOX-1 expression/activation or STBEVs could adversely affect vascular function and contribute to vascular complications of pregnancy.


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