scholarly journals Glycated collagen cross-linking alters cardiac mechanics in volume-overload hypertrophy

2003 ◽  
Vol 284 (4) ◽  
pp. H1277-H1284 ◽  
Author(s):  
Keith L. Herrmann ◽  
Andrew D. McCulloch ◽  
Jeffrey H. Omens
Keyword(s):  
Volume Overload ◽  
Cardiac Mechanics ◽  
Left Ventricular ◽  
Cross Linking ◽  
Collagen Concentration ◽  
Longitudinal Stiffness ◽  
Diastolic Compliance ◽  
Cross Links ◽  
Modify Collagen ◽  
Collagen Cross Linking

Alteration of hemodynamic loading induces remodeling that includes changes in myocardial properties and extracellular matrix structure. We investigated the hypothesis that cardiac hypertrophy due to volume overload produces changes in myocardial diastolic mechanics and stiffness that are in part due to alterations in advanced glycation end-product (AGE) collagen cross-linking. Rats developed volume overload induced by arteriovenous fistula (AVF). To assess the dependence of AGE cross-linking on mechanics, we prevented AGE formation by administering the drug aminoguanidine (AG) to one group of AVF rats (AG+AVF). Volume overload did not modify collagen concentration. Right ventricular AGE cross-links were modestly elevated in AVF hearts but were significantly reduced by AG. AVF rats exhibited significantly increased septal AGE cross-links that were inhibited in the AG+AVF group. AVF-induced increases in left ventricular longitudinal stiffness and septal circumferential stiffness were prevented in AG+AVF hearts. Volume overload appears to regionally modify AGE collagen cross-linking and stiffness, and AG treatment prevented these increases, demonstrating that AGE cross-linking plays a role in mediating diastolic compliance in volume-overload hypertrophy.

Unloading-induced remodeling in the normal and hypertrophic left ventricle

2003 ◽  
Vol 284 (6) ◽  
pp. H2061-H2068 ◽  
Author(s):  
Brian S. McGowan ◽  
Christopher B. Scott ◽  
Anbin Mu ◽  
Richard J. McCormick ◽  
D. Paul Thomas ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Small Animal ◽  
Left Ventricular ◽  
Reverse Remodeling ◽  
Cross Linking ◽  
Heterotopic Transplantation ◽  
Collagen Concentration ◽  
Matrix Interactions ◽  
Normal Controls ◽  
Collagen Cross Linking

To date, no study has assessed the degree of similarity between left ventricular (LV) reverse remodeling and atrophic remodeling. Stable LV hypertrophy was induced by creation of an arteriovenous fistula (AVF) in Lewis rats (32 days). LV unloading was induced by heterotopic transplantation of normal (NL-HT) and/or hypertrophic (AVF-HT) hearts (7 days). We compared indexes of remodeling in AVF, NL-HT, and AVF-HT groups with those of normal controls. LV unloading induced decreases in cardiomyocyte size in NL-HT and AVF-HT hearts. NL-HT and AVF-HT LV were both characterized by relative increases in collagen concentration that were largely a reflection of decreases in myocyte volume. NL-HT and AVF-HT LV were associated with similar increases in matrix metalloproteinase (MMP-2 and -9) zymographic activity, without change in the abundance of the tissue inhibitors of the MMPs. In contrast, AVF-HT, but not NL-HT, was associated with a dramatic increase in collagen cross-linking. Our findings suggest an overall similarity in the response of the normal and hypertrophic LV to surgical unloading. However, the dramatic increase in collagen cross-linking after just 1 wk of unloading suggests a potential difference in the dynamics of collagen metabolism between the two models. Further studies will be required to determine the precise molecular mechanisms responsible for these differences in extracellular matrix regulation. However, with respect to these and related issues, heterotopic transplantation of hypertrophied hearts will be a useful small animal model for defining mechanisms of myocyte-matrix interactions during decreased loading conditions.

scholarly journals Overhydroxylation of Lysine of Collagen Increases Uterine Fibroids Proliferation: Roles of Lysyl Hydroxylases, Lysyl Oxidases, and Matrix Metalloproteinases

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Marwa Kamel ◽  
Mohamed Wagih ◽  
Gokhan S. Kilic ◽  
Concepcion R. Diaz-Arrastia ◽  
Mohamed A. Baraka ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Treatment Options ◽  
Uterine Fibroids ◽  
Cross Linking ◽  
Ki 67 ◽  
Subsequent Formation ◽  
Lysyl Oxidases ◽  
Cross Links ◽  
Collagen Cross Linking

The role of the extracellular matrix (ECM) in uterine fibroids (UF) has recently been appreciated. Overhydroxylation of lysine residues and the subsequent formation of hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) cross-links underlie the ECM stiffness and profoundly affect tumor progression. The aim of the current study was to investigate the relationship between ECM of UF, collagen and collagen cross-linking enzymes [lysyl hydroxylases (LH) and lysyl oxidases (LOX)], and the development and progression of UF. Our results indicated that hydroxyl lysine (Hyl) and HP cross-links are significantly higher in UF compared to the normal myometrial tissues accompanied by increased expression of LH (LH2b) and LOX. Also, increased resistance to matrix metalloproteinases (MMP) proteolytic degradation activity was observed. Furthermore, the extent of collagen cross-links was positively correlated with the expression of myofibroblast marker (α-SMA), growth-promoting markers (PCNA; pERK1/2;FAKpY397; Ki-67; and Cyclin D1), and the size of UF. In conclusion, our study defines the role of overhydroxylation of collagen and collagen cross-linking enzymes in modulating UF cell proliferation, differentiation, and resistance to MMP. These effects can establish microenvironment conducive for UF progression and thus represent potential target treatment options of UF.

scholarly journals Chemistry of collagen cross-linking: biochemical changes in collagen during the partial mineralization of turkey leg tendon

1997 ◽  
Vol 322 (2) ◽  
pp. 535-542 ◽  
Author(s):  
Lynda KNOTT ◽  
John F. TARLTON ◽  
Allen J. BAILEY
Keyword(s):  
Collagen Matrix ◽  
Cross Linking ◽  
Cross Link ◽  
Lysine Residues ◽  
Collagen Mineralization ◽  
Cross Links ◽  
The Cross ◽  
Calcified Tissues ◽  
Turkey Leg Tendon ◽  
Collagen Cross Linking

With age, the proximal sections of turkey leg tendons become calcified, and this phenomenon has led to their use as a model for collagen mineralization. Mineralizing turkey leg tendon was used in this study to characterize further the composition and cross-linking of collagen in calcified tissues. The cross-link profiles of mineralizing collagen are significantly different from those of other collagenous matrices with characteristically low amounts of hydroxylysyl-pyridinoline and the presence of lysyl-pyridinoline and pyrrolic cross-links. However, the presence of the immature cross-link precursors previously reported in calcifying tissues was not supported in the present study, and was found to be due to the decalcification procedure using EDTA. Analysis of tendons from young birds demonstrated differences in the cross-link profile which indicated a higher level of hydroxylation of specific triple-helical lysines involved in cross-linking of the proximal tendon. This may be related to later calcification, suggesting that this part of the tendon is predestined to be calcified. The minimal changes in lysyl hydroxylation in both regions of the tendon with age were in contrast with the large changes in the cross-link profile, indicating differential hydroxylation of the helical and telopeptide lysine residues. Changes with age in the collagen matrix, its turnover and thermal properties in both the proximal and distal sections of the tendon clearly demonstrate that a new and modified matrix is formed throughout the tendon, and that a different type of matrix is formed at each site.

scholarly journals Moderate Loss of the Extracellular Matrix Proteoglycan Lumican Attenuates Cardiac Fibrosis in Mice Subjected to Pressure Overload

Cardiology ◽  
2020 ◽  
Vol 145 (3) ◽  
pp. 187-198 ◽  
Author(s):  
Naiyereh Mohammadzadeh ◽  
Arne Olav Melleby ◽  
Sheryl Palmero ◽  
Ivar Sjaastad ◽  
Shukti Chakravarti ◽  
...  
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Diastolic Dysfunction ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cross Linking ◽  
Myocardial Remodeling ◽  
Functional Changes ◽  
Collagen Cross Linking

Introduction: The heart undergoes myocardial remodeling during progression to heart failure following pressure overload. Myocardial remodeling is associated with structural and functional changes in cardiac myocytes, fibroblasts, and the extracellular matrix (ECM) and is accompanied by inflammation. Cardiac fibrosis, the accumulation of ECM molecules including collagens and collagen cross-linking, contributes both to impaired systolic and diastolic function. Insufficient mechanistic insight into what regulates cardiac fibrosis during pathological conditions has hampered therapeutic so­lutions. Lumican (LUM) is an ECM-secreted proteoglycan known to regulate collagen fibrillogenesis. Its expression in the heart is increased in clinical and experimental heart failure. Furthermore, LUM is important for survival and cardiac remodeling following pressure overload. We have recently reported that total lack of LUM increased mortality and left ventricular dilatation, and reduced collagen expression and cross-linking in LUM knockout mice after aortic banding (AB). Here, we examined the effect of LUM on myocardial remodeling and function following pressure overload in a less extreme mouse model, where cardiac LUM level was reduced to 50% (i.e., moderate loss of LUM). Methods and Results: mRNA and protein levels of LUM were reduced to 50% in heterozygous LUM (LUM+/–) hearts compared to wild-type (WT) controls. LUM+/– mice were subjected to AB. There was no difference in survival between LUM+/– and WT mice post-AB. Echocardiography revealed no striking differences in cardiac geometry between LUM+/– and WT mice 2, 4, and 6 weeks post-AB, although markers of diastolic dysfunction indicated better function in LUM+/– mice. LUM+/– hearts revealed reduced cardiac fibrosis assessed by histology. In accordance, the expression of collagen I and III, the main fibrillar collagens in the heart, and other ECM molecules central to fibrosis, i.e. including periostin and fibronectin, was reduced in the hearts of LUM+/– compared to WT 6 weeks post-AB. We found no differences in collagen cross-linking between LUM+/– and WT mice post-AB, as assessed by histology and qPCR. Conclusions: Moderate lack of LUM attenuated cardiac fibrosis and improved diastolic dysfunction following pressure overload in mice, adding to the growing body of evidence suggesting that LUM is a central profibrotic molecule in the heart that could serve as a potential therapeutic target.

Collagen cross-linking mediated by lysyl hydroxylase 2: an enzymatic battlefield to combat fibrosis

2019 ◽  
Vol 63 (3) ◽  
pp. 377-387 ◽  
Author(s):  
Bram Piersma ◽  
Ruud A. Bank
Keyword(s):  
Organ Failure ◽  
Molecular Basis ◽  
Repair Process ◽  
Cross Linking ◽  
Collagen Network ◽  
Lysyl Hydroxylase ◽  
Cross Links ◽  
Collagen Cross Linking ◽  
Excessive Accumulation

Abstract The hallmark of fibrosis is an excessive accumulation of collagen, ultimately leading to organ failure. It has become evident that the deposited collagen also exhibits qualitative modifications. A marked modification is the increased cross-linking, leading to a stabilization of the collagen network and limiting fibrosis reversibility. Not only the level of cross-linking is increased, but also the composition of cross-linking is altered: an increase is seen in hydroxyallysine-derived cross-links at the expense of allysine cross-links. This results in irreversible fibrosis, as collagen cross-linked by hydroxyallysine is more difficult to degrade. Hydroxyallysine is derived from a hydroxylysine in the telopeptides of collagen. The expression of lysyl hydroxylase (LH) 2 (LH2), the enzyme responsible for the formation of telopeptidyl hydroxylysine, is universally up-regulated in fibrosis. It is expected that inhibition of this enzyme will lead to reversible fibrosis without interfering with the normal repair process. In this review, we discuss the molecular basis of collagen modifications and cross-linking, with an emphasis on LH2-mediated hydroxyallysine cross-links, and their implications for the pathogenesis and treatment of fibrosis.

Collagen Cross-linking and Ultimate Tensile Strength in Dentin

2004 ◽  
Vol 83 (10) ◽  
pp. 807-810 ◽  
Author(s):  
P.A. Miguez ◽  
P.N.R. Pereira ◽  
P. Atsawasuwan ◽  
M. Yamauchi
Keyword(s):  
Tensile Strength ◽  
Ultimate Tensile Strength ◽  
Dental Materials ◽  
Cross Linking ◽  
Anatomical Location ◽  
Dentinal Tubules ◽  
Root Dentin ◽  
Cross Links ◽  
The Difference ◽  
Collagen Cross Linking

Several studies have indicated differences in bond strength of dental materials to crown and root dentin. To investigate the potential differences in matrix properties between these locations, we analyzed upper root and crown dentin in human third molars for ultimate tensile strength and collagen biochemistry. In both locations, tensile strength tested perpendicular to the direction of dentinal tubules (undemineralized crown = 140.4 ± 48.6/root = 95.9 ± 26.1; demineralized crown = 16.6 ± 6.3/root = 29.0 ± 12.4) was greater than that tested parallel to the tubular direction (undemineralized crown = 73.1 ± 21.2/root = 63.2 ± 22.6; demineralized crown = 9.0 ± 3.9/root = 16.2 ± 8.0). The demineralized specimens showed significantly greater tensile strength in root than in crown. Although the collagen content was comparable in both locations, two major collagen cross-links, dehydrodihydroxylysinonorleucine/its ketoamine and pyridinoline, were significantly higher in the root (by ~ 30 and ~ 55%, respectively) when compared with those in the crown. These results indicate that the profile of collagen cross-linking varies as a function of anatomical location in dentin and that the difference may partly explain the site-specific tensile strength.

scholarly journals Age-related changes in the physical properties, cross-linking, and glycation of collagen from mouse tail tendon

2020 ◽  
Vol 295 (31) ◽  
pp. 10562-10571 ◽  
Author(s):  
Melanie Stammers ◽  
Irina M. Ivanova ◽  
Izabella S. Niewczas ◽  
Anne Segonds-Pichon ◽  
Matthew Streeter ◽  
...  
Keyword(s):  
The Other ◽  
Cross Linking ◽  
Structural Protein ◽  
Cross Link ◽  
Age Related ◽  
Cross Links ◽  
Tail Tendon ◽  
Collagen Cross Linking ◽  
Age Related Changes ◽  
Tendon Collagen

Collagen is a structural protein whose internal cross-linking critically determines the properties and functions of connective tissue. Knowing how the cross-linking of collagen changes with age is key to understanding why the mechanical properties of tissues change over a lifetime. The current scientific consensus is that collagen cross-linking increases with age and that this increase leads to tendon stiffening. Here, we show that this view should be reconsidered. Using MS-based analyses, we demonstrated that during aging of healthy C57BL/6 mice, the overall levels of collagen cross-linking in tail tendon decreased with age. However, the levels of lysine glycation in collagen, which is not considered a cross-link, increased dramatically with age. We found that in 16-week-old diabetic db/db mice, glycation reaches levels similar to those observed in 98-week-old C57BL/6 mice, while the other cross-links typical of tendon collagen either decreased or remained the same as those observed in 20-week-old WT mice. These results, combined with findings from mechanical testing of tendons from these mice, indicate that overall collagen cross-linking in mouse tendon decreases with age. Our findings also reveal that lysine glycation appears to be an important factor that contributes to tendon stiffening with age and in diabetes.

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

2013 ◽  
Vol 126 (1) ◽  
pp. 85-94 ◽  
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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