Pro-fibrotic effect of oxidized LDL in cardiac myofibroblasts

Villa, Monica; Cerda-Opazo, Paulina; Jimenez-Gallegos, Danica; Garrido-Moreno, Valeria; Chiong, Mario; Quest, Andrew F. G.; Alonso, Jorge R. Toledo; Garcı́a, Lorena

doi:10.1016/j.bbrc.2020.01.156

Cited by 13 publications

(7 citation statements)

References 22 publications

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“…Experimental studies have implicated LOX-1 in cardiac fibrosis and heart failure [ 32 , 33 ]. To explore possible clinical evidence for a role of LOX-1 in heart failure we compared baseline sLOX-1 levels in subjects that did not have an incident myocardial infarction but developed heart failure during follow-up ( n = 189) with those who did not ( n = 4432).…”

Section: Resultsmentioning

confidence: 99%

Elevated soluble LOX-1 predicts risk of first-time myocardial infarction

Schiopu,

Björkbacka,

Narasimhan

et al. 2023

Annals of Medicine

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Background There is an unmet clinical need for novel therapies addressing the residual risk in patients receiving guideline preventive therapy for coronary heart disease. Experimental studies have identified a pro-atherogenic role of the oxidized LDL receptor LOX-1. We investigated the association between circulating soluble LOX-1 (sLOX-1) and the risk for development of myocardial infarction. Methods The study subjects ( n = 4658) were part of the Malmö Diet and Cancer study. The baseline investigation was carried out 1991-1994 and the incidence of cardiovascular events monitored through national registers during a of 19.5 ± 4.9 years follow-up. sLOX-1 and other biomarkers were analyzed by proximity extension assay and ELISA in baseline plasma. Results Subjects in the highest tertile of sLOX-1 had an increased risk of myocardial infarction (hazard ratio (95% CI) 1.76 (1.40-2.21) as compared with those in the lowest tertile. The presence of cardiovascular risk factors was related to elevated sLOX-1, but the association between sLOX-1 and risk of myocardial infarction remained significant when adjusting for risk factors. Conclusions In this prospective population study we found an association between elevated sLOX-1, the presence of carotid disease and the risk for first-time myocardial infarction. Taken together with previous experimental findings of a pro-atherogenic role of LOX-1, this observation supports LOX-1 inhibition as a possible target for prevention of myocardial infarction.

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Section: Resultsmentioning

confidence: 99%

Elevated soluble LOX-1 predicts risk of first-time myocardial infarction

Schiopu,

Björkbacka,

Narasimhan

et al. 2023

Annals of Medicine

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“…In addition, ox-LDL has been shown to have an LOX-1-dependent profibrotic effect in cardiac myofibroblasts, because this effect could be abolished by LOX-1 knockdown. 23 LOX-1 knockdown has also been shown to significantly ameliorate cardiac cell hypertrophy through a reduction in reactive oxygen species. 24 Increased serum levels of soluble LOX-1 accompanied by elevated ox-LDL levels have been reported in patients with nonalcoholic fatty liver disease, indicating the significant role of LOX-1 in modulating ox-LDL.…”

Section: Discussionmentioning

confidence: 99%

Ezetimibe treatment reduces oxidized low-density lipoprotein in biliary cirrhotic rats

Chang,

Huang,

Hsu

et al. 2024

Journal of the Chinese Medical Association

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Background: In liver cirrhosis, chronic inflammation is associated with an increase in oxidative stress, and subsequently an increase in the concentration of oxidized low-density lipoprotein (ox-LDL). Ezetimibe is a lipid-lowering agent with anti-inflammation and anti-oxidative stress activities. This study aimed to investigate the effect of ezetimibe treatment on ox-LDL in cirrhotic rats. Methods: Biliary cirrhosis was induced in Sprague-Dawley rats with common bile duct ligation (BDL). Sham-operated rats served as surgical controls. Ezetimibe (10 mg/kg/day) or vehicle was administered in the sham-operated or BDL rats for 4 weeks, after which hemodynamic parameters, biochemistry data, oxidative stress were evaluated. Plasma and intrahepatic ox-LDL levels were also examined, and hepatic proteins were analyzed to explore the mechanism of ezetimibe treatment. Results: The BDL rats had typical features of cirrhosis including jaundice, impaired liver function, hyperlipidemia and elevated ox-LDL levels compared to the sham-operated rats. Ezetimibe treatment did not affect hemodynamics, liver biochemistry or plasma lipid levels. However, it significantly reduced oxidative stress, plasma levels of ox-LDL and tumor necrosis factor α. In addition, ezetimibe upregulated the hepatic protein expression of an ox-LDL scavenger (lectin-like oxidized low-density lipoprotein rececptor-1), which resulted in reductions in intrahepatic ox-LDL and fat accumulation in the BDL rats. Nevertheless, ezetimibe treatment did not ameliorate hepatic inflammation or liver fibrosis. Conclusion: Ezetimibe reduced plasma and intrahepatic ox-LDL levels in the cirrhotic rats. Furthermore, it ameliorated intrahepatic fat accumulation and oxidative stress. However, ezetimibe did not alleviate hepatic fibrosis or inflammation in the biliary cirrhotic rats.

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“…Also the pro-fibrotic effects of oxLDL, following LOX-1 binding, has been studied: oxLDL stimulates TGFβ1 expression and Smad pathway activation, increasing the synthesis and secretion of extracellular matrix proteins (370) (371).…”

Section: Ros-mediated Low Density Lipoprotein Oxidationmentioning

confidence: 99%

2288Oxidized LDL/CD36/PPARg circuitry is a trigger of adipogenesis in arrhythmogenic cardiomyopathy

Stadiotti

Sommariva

Casella

et al. 2019

European Heart Journal

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Background Arrhythmogenic Cardiomyopathy (ACM) is a genetic condition hallmarked by ventricular fibro-fatty replacement and arrhythmias. Cardiac mesenchymal stromal cells (C-MSC) differentiate into adipocytes in ACM hearts, through the activation of PPARγ, caused by ACM mutations (e.g. PKP2). The clinical phenotype of ACM is variable for poorly understood reasons. The only recognized cofactor is physical exercise, which is known to increases oxidative stress. An accepted marker of exercise-induced oxidative stress is 13HODE, a component of oxLDL and direct activator of PPARγ. In macrophages, during foam cell formation, 13HODE creates a feed-forward loop increasing both PPARγ and the oxLDL receptor CD36, resulting in fat accumulation. Purpose To investigate oxLDL effects on ACM adipogenesis and to dissect the involved pathways. Methods We analyzed plasmas (n=42) and ventricular tissues (n=4) of ACM patients and matched healthy controls (HC). For in vitro experiments, ACM and HC C-MSC (n=10) have been used, while in vivo experiments have been conducted in heterozygous Pkp2 knock-out mice (Pkp2+/−; n=10). Results We observed higher plasma oxLDL in ACM patients compared to HC (ACM 246.70±55.89 vs HC 102.5±17.95ng/ml; p=0.019). oxLDL levels also discriminate between ACM patients with overt phenotype and their unaffected relatives carriers of the same causative mutations (p=0.03). We observed higher oxidative stress (MDA intensity 40.87±11.76 fold; p=0.015) and CD36 levels (14.72±2.10 fold; p=0.0007) in ACM ventricular tissue, compared to HC. In basal conditions, ACM C-MSC showed greater oxidative stress (MDA intensity 8.83±2.78 fold p=0.017) and higher expression of PPARγ (1.47±0.14 fold; p=0.009) compared to HC C-MSC. The adipogenic stimulation led to a parallel increase of CD36 and lipid accumulation, mainly in ACM C-MSC (slopes statistically different p=0.016). OxLDL and 13HODE administration increased lipid accumulation in ACM C-MSC (ORO staining ACM vs ACM+oxLDL p=0.01; ACM vs ACM+13HODE p=0.014). On the contrary, the antioxidant N-Acetylcysteine (NAC) prevented lipid accumulation in ACM C-MSC (ORO staining ACM+13HODE vs ACM+13HODE+NAC p=0.0009). Through CD36 silencing of ACM C-MSC, we obtained a significantly lower lipid accumulation than non-silenced cells (ORO staining 0.35±0.10 fold; p=0.003). Pkp2+/− mice do not spontaneously accumulate adipocytes in the heart, however Pkp2+/− C-MSC are more prone to lipid accumulation in vitro than WT cells (p=0.007). Accordingly, mice have low plasma oxLDL and cardiac oxidative stress. By increasing plasma cholesterol and oxidative stress through high fat diet, we observed fibro-fatty substitution in Pkp2+/− hearts (p=0.046). Figure 1 Conclusions These findings reveal a modulatory role of oxidized lipids in ACM adipogenesis at a cellular, tissue and clinical level, enlightening novel targets for pharmacological strategies to prevent adipogenic substitution and consequent ACM clinical phenotypes. Acknowledgement/Funding Telethon Foundation; Italian Ministry of Health

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Pro-fibrotic effect of oxidized LDL in cardiac myofibroblasts

Cited by 13 publications

References 22 publications

Elevated soluble LOX-1 predicts risk of first-time myocardial infarction

Elevated soluble LOX-1 predicts risk of first-time myocardial infarction

Ezetimibe treatment reduces oxidized low-density lipoprotein in biliary cirrhotic rats

2288Oxidized LDL/CD36/PPARg circuitry is a trigger of adipogenesis in arrhythmogenic cardiomyopathy

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