596 TARGETING OF LYSYL OXIDASE-LIKE-2 (LOXL2) PROMOTES REVERSAL OF LIVER FIBROSIS VIA INHIBITION OF COLLAGEN CROSS-LINKING AND FIBROTIC MATRIX STABILIZATION

Collagen biosynthesis was analyzed in C57BL/6J mice homozygous for the high-growth locus. Plasma levels of insulin-like growth factor-1 (IGF-1) were significantly elevated in high-growth mice at all ages studied (3 wk-6 mo); IGF-binding proteins were also elevated. Skin biopsies were obtained from mice aged 3, 6, and 9 wk under halothane anesthesia. Mice were killed at 6 mo of age. Collagen, expressed per weight of tissue, was significantly increased in all tissues from high-growth mice, as was collagen cross-linking, expressed as moles of cross-link per mole of collagen. Expression of types I and III collagen, lysyl oxidase, and lysyl hydroxylase was increased in all tissues analyzed. There was a preferential increase in type III expression relative to type I expression. Rate and extent of accumulation of collagen in granulation tissue were measured in polyvinyl alcohol sponges implanted subcutaneously; collagen accumulation was significantly greater in the high-growth mice. These results suggest that 1) elevated circulating IGF-1 may increase collagen deposition both in normal tissue as well as in granulation tissue by increasing collagen gene expression, 2) IGF-1 may increase collagen cross-linking by stimulating expression of lysyl oxidase, and 3) the preferential increase in dihydroxylated cross-links observed in high-growth mice may be due to the stimulation of lysyl hydroxylase expression by IGF-1. In summary, elevated levels of IGF-1 appear to affect collagen both quantitatively and qualitatively, primarily through their effects on gene expression of collagen and of those enzymes responsible for posttranslational modifications of collagen.

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Lysyl Oxidase Expression and Collagen Cross-Linking during Chronic Adriamycin Nephropathy

Nephron ◽

10.1159/000190168 ◽

1997 ◽

Vol 76 (2) ◽

pp. 192-200 ◽

Cited By ~ 44

Author(s):

Armando Di Donato ◽

Gian Marco Ghiggeri ◽

Marco Di Duca ◽

Elena Jivotenko ◽

Roberto Acinni ◽

...

Keyword(s):

Lysyl Oxidase ◽

Cross Linking ◽

Adriamycin Nephropathy ◽

Collagen Cross Linking

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Loss of fibulin-4 results in abnormal collagen fibril assembly in bone, caused by impaired lysyl oxidase processing and collagen cross-linking

Matrix Biology ◽

10.1016/j.matbio.2015.12.002 ◽

2016 ◽

Vol 50 ◽

pp. 53-66 ◽

Cited By ~ 12

Author(s):

Takako Sasaki ◽

Reinout Stoop ◽

Takao Sakai ◽

Andreas Hess ◽

Rainer Deutzmann ◽

...

Keyword(s):

Collagen Fibril ◽

Lysyl Oxidase ◽

Cross Linking ◽

Collagen Cross Linking

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N-acetyl-seryl-aspartyl-lysyl-proline reduces cardiac collagen cross-linking and inflammation in angiotensin II-induced hypertensive rats

Clinical Science ◽

10.1042/cs20120619 ◽

2013 ◽

Vol 126 (1) ◽

pp. 85-94 ◽

Cited By ~ 35

Author(s):

Germán E. González ◽

Nour-Eddine Rhaleb ◽

Pablo Nakagawa ◽

Tang-Dong Liao ◽

Yunhe Liu ◽

...

Keyword(s):

Angiotensin Ii ◽

Transforming Growth Factor ◽

Nuclear Translocation ◽

Lysyl Oxidase ◽

Left Ventricular ◽

Cross Linking ◽

Lymphocyte Infiltration ◽

Total Collagen ◽

Induced Hypertension ◽

Collagen Cross Linking

We have reported previously that Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) reduces fibrosis and inflammation (in macrophages and mast cells). However, it is not known whether Ac-SDKP decreases collagen cross-linking and lymphocyte infiltration; lymphocytes modulate both collagen cross-linking and ECM (extracellular matrix) formation in hypertension. Thus we hypothesized that (i) in AngII (angiotensin II)-induced hypertension, Ac-SDKP prevents increases in cross-linked and total collagen by down-regulating LOX (lysyl oxidase), the enzyme responsible for cross-linking, and (ii) these effects are associated with decreased pro-fibrotic cytokine TGFβ (transforming growth factor β) and the pro-inflammatory transcription factor NF-κB (nuclear factor κB) and CD4+/CD8+ lymphocyte infiltration. We induced hypertension in rats by infusing AngII either alone or combined with Ac-SDKP for 3 weeks. Whereas Ac-SDKP failed to lower BP (blood pressure) or LV (left ventricular) hypertrophy, it did prevent AngII-induced increases in (i) cross-linked and total collagen, (ii) LOX mRNA expression and LOXL1 (LOX-like 1) protein, (iii) TGFβ expression, (iv) nuclear translocation of NF-κB, (v) CD4+/CD8+ lymphocyte infiltration, and (vi) CD68+ macrophages infiltration. In addition, we found a positive correlation between CD4+ infiltration and LOXL1 expression. In conclusion, the effect of Ac-SDKP on collagen cross-linking and total collagen may be due to reduced TGFβ1, LOXL1, and lymphocyte and macrophage infiltration, and its effect on inflammation could be due to lower NF-κB.

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