Effects of oxidized low-density lipoproteins on the hepatic microvasculature

Oteiza, Ana; Li, Ruomei; McCuskey, Robert S.; Smedsrød, Bård; Sørensen, Karen Kristine

doi:10.1152/ajpgi.00347.2010

Cited by 20 publications

(17 citation statements)

References 60 publications

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“…These findings were also present in 2 patients with early SSc 12 but not in a patient with RP without capillary nailbed changes. Thus, these features suggest oxidative injury and endothelial dysfunction, and establish SSc as a disease of the endothelium 37 . Under standing the link between endothelium dysfunction and interstitial edema has diagnostic and therapeutic implications.…”

Section: Discussionmentioning

confidence: 95%

Vascular Leak Is a Central Feature in the Pathogenesis of Systemic Sclerosis

Frech¹,

Revelo²,

Drakos³

et al. 2012

J Rheumatol

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Objective The main histopathological focus of systemic sclerosis (SSc) has concentrated on fibrotic changes. We investigated the microvasculature alterations in the skin of patients with SSc at various stages of disease duration with whole-field digital microscopy. Methods Twenty consecutive patients with SSc, 1 with Raynaud's phenomenon (RP) without SSc, and 4 healthy controls underwent punch biopsy on the medial forearm. Eighteen patients were included in the primary analysis. Two with recent-onset diffuse cutaneous disease, 1 repeat SSc biopsy, and 1 patient with RP without SSc were also evaluated. All specimens were processed with histochemical stains and immunohistochemistry. We analyzed microvasculature abnormalities in an objective and systematic manner taking advantage of recent advances in whole-field digital microscopy. This analysis was coupled with ultrastructural evaluation performed with transmission electron microscopy (TEM). Results Whole-field digital microscopy and TEM of SSc skin biopsies revealed that endothelial abnormalities are a universal feature regardless of clinical features and/or duration of disease. These features were not seen in any healthy control specimens or in the single RP patient samples. Whole-field digital microscopy identified increased interstitial edema (31.0% ± 9.6% vs 17.6% ± 3.3% in controls; p = 0.009) and fibrosis (75.6% ± 5.7% vs 66.1% ± 9.8% in controls; p = 0.02) in all patients with SSc. Lower CD34 staining was seen in SSc compared to healthy controls (0.32% ± 0.22% vs 1.31% ± 0.34%; p < 0.0001) and within the SSc population with interstitial lung disease (0.55% ± 0.22% vs 0.15% ± 0.16%; p = 0.01). Perivascular and interstitial infiltrate of mast cells was present in all SSc specimens. Conclusion Whole-field digital microscopy offers a means of rapidly carrying out objective, fully quantitative, and reproducible measurements of microscopic features of SSc microvascular change. The universal morphologically abnormal endothelial cells and interstitial edema in all patients with SSc biopsied suggests that SSc may be intrinsically a disease of the endothelium characterized by vascular leak.

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Section: Discussionmentioning

confidence: 95%

Vascular Leak Is a Central Feature in the Pathogenesis of Systemic Sclerosis

Frech¹,

Revelo²,

Drakos³

et al. 2012

J Rheumatol

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“…Activated LSEC upregulates the cellular adhesion molecules ICAM-1, VCAM-1, and VAP-1, which recruit blood leucocytes, losing their physiological barrier capacity and leading to entry of circulating leucocytes within the liver parenchyma. LSEC are then transformed from mediators of tolerance to potent stimulators of immunity and become a critical component of intrahepatic inflammation [93,[97][98][99][100][101][102][103][104][105][106][107].…”

Section: Loss Of Anti-inflammatory Capacitiesmentioning

confidence: 99%

The Endothelium as a Driver of Liver Fibrosis and Regeneration

Lafoz

Ruart

Anton

et al. 2020

Cells

105

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Liver fibrosis is a common feature of sustained liver injury and represents a major public health problem worldwide. Fibrosis is an active research field and discoveries in the last years have contributed to the development of new antifibrotic drugs, although none of them have been approved yet. Liver sinusoidal endothelial cells (LSEC) are highly specialized endothelial cells localized at the interface between the blood and other liver cell types. They lack a basement membrane and display open channels (fenestrae), making them exceptionally permeable. LSEC are the first cells affected by any kind of liver injury orchestrating the liver response to damage. LSEC govern the regenerative process initiation, but aberrant LSEC activation in chronic liver injury induces fibrosis. LSEC are also main players in fibrosis resolution. They maintain liver homeostasis and keep hepatic stellate cell and Kupffer cell quiescence. After sustained hepatic injury, they lose their phenotype and protective properties, promoting angiogenesis and vasoconstriction and contributing to inflammation and fibrosis. Therefore, improving LSEC phenotype is a promising strategy to prevent liver injury progression and complications. This review focuses on changes occurring in LSEC after liver injury and their consequences on fibrosis progression, liver regeneration, and resolution. Finally, a synopsis of the available strategies for LSEC-specific targeting is provided.

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“…It is noted that there is a close association between the HFD and oxLDL. Although oxLDL is rapidly removed by Kupffer cells and endothelial cells in the liver [37], intravenous injection of oxLDL induces several changes in the liver microvasculature that may lead to sinusoidal endothelial dysfunction [38], which is considered as an early event in the progression of nonalcoholic steatohepatitis (NASH) [39]. Both HFD and oxLDL play an important role in the initiation of NASH pathogenesis [40].…”

Section: Discussionmentioning

confidence: 99%

Fibronectin Type III Domain-Containing 5 Attenuates Liver Fibrosis Via Inhibition of Hepatic Stellate Cell Activation

Zhou

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Fibronectin type III domain-containing 5 (FNDC5) protein is involved in the beneficial effects of exercise on metabolism. FNDC5 attenuates hepatic steatosis induced by high fat diet (HFD). Here, we examined the effects of FNDC5 on liver fibrosis and underline mechanisms. Methods: Experiments were carried out on wild-type and FNDC5^-/- mice, primary mouse hepatic stellate cells (HSCs) and human hepatic stellate cell line (LX-2). The mice were fed with HFD for 6 months to induce liver fibrosis. Oxidized low density lipoprotein (oxLDL) were used to induce the activation of hepatic stellate cells and fibrosis in mouse HSCs and human LX-2 cells. H&E, Masson’s trichrome staining and Sirius red staining were used for liver sections. Protein and mRNA expressions were evaluated with Western blot and RT-PCR, respectively. Results: FNDC5 deficiency aggravated the HFD-induced liver fibrosis and HSCs activation in mice. It exacerbated the HFD-induced inhibition of AMPK phosphorylation, upregulation of connective tissue growth factor (CTGF) and transforming growth factor-β (TGF-β), and deposition of extracellular matrix (ECM) in liver of mice. Administration of FNDC5 attenuated oxLDL-induced AMPK deactivation, HSCs activation, CTGF and TGF-β upregulation and ECM deposition in mouse HSCs. The beneficial effects of FNDC5 on oxLDL-induced AMPK dephosphorylation, HSCs activation and ECM deposition were prevented by the inhibition of AMPK with compound C in human LX-2 cells. However, the effects of FNDC5 on hepatic fibrosis in vivo in this study cannot be distinguished from its effects on adiposity and hepatic steatosis. Conclusions: FNDC5 deficiency aggravates HFD-induced liver fibrosis in mice. FNDC5 plays beneficial roles in attenuating liver fibrosis via AMPK phosphorylation-mediated inhibition of HSCs activation.

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Effects of oxidized low-density lipoproteins on the hepatic microvasculature

Abstract: Oteiza A, Li R, McCuskey RS, Smedsrød B, Sørensen KK. Effects of oxidized low-density lipoproteins on the hepatic microvasculature.

Cited by 20 publications

References 60 publications

Vascular Leak Is a Central Feature in the Pathogenesis of Systemic Sclerosis

Vascular Leak Is a Central Feature in the Pathogenesis of Systemic Sclerosis

The Endothelium as a Driver of Liver Fibrosis and Regeneration

Fibronectin Type III Domain-Containing 5 Attenuates Liver Fibrosis Via Inhibition of Hepatic Stellate Cell Activation

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