Copper deficiency alters collagen types and covalent cross-linking in swine myocardium and cardiac valves

1993 ◽  
Vol 264 (6) ◽  
pp. H2154-H2161 ◽  
Author(s):  
R. K. Vadlamudi ◽  
R. J. McCormick ◽  
D. M. Medeiros ◽  
J. Vossoughi ◽  
M. L. Failla
Keyword(s):  
Cardiac Hypertrophy ◽  
Copper Deficiency ◽  
Left Ventricular ◽  
Cross Linking ◽  
Type Iii Collagen ◽  
Cardiac Valves ◽  
Dietary Copper ◽  
Organ Systems ◽  
The Impact ◽  
Collagen Cross Linking

Dietary copper deficiency induces alterations of connective tissue metabolism that are associated with lesions in cardiovascular and other organ systems. To determine the impact of copper deficiency on characteristics of collagen in porcine myocardium and cardiac valves, weaned pigs were fed diets with adequate or deficient levels of copper. Although dietary copper did not affect the concentration of collagen in either myocardium or bicuspid valves, the degree of collagen cross-linking, as assessed by the level of hydroxylysylpyridinoline, was lower in both tissues of copper-deficient pigs. Proportions of type III collagen were increased in the left ventricle and bicuspid valves of copper-deficient pigs. Copper deficiency induced extensive remodeling, however, of the collagen fraction of cardiac interstitium. Reduction in left ventricular collagen cross-linking may provide the stimulus for the development of cardiac hypertrophy, which characterizes severe copper deficiency, by increasing the compliance of the ventricular wall. The shift in the phenotypic profile of collagen that is associated with this cardiac hypertrophy indicates synthesis of new collagen, which could affect collagen cross-linking irrespective of copper status.

Glycosylated CD147 reduces myocardial collagen cross-linking in cardiac hypertrophy

2018 ◽  
Vol 119 (10) ◽  
pp. 8022-8034 ◽  
Author(s):  
Ning-Yu Ru ◽  
Long-Biao Cui ◽  
Bo Jiao ◽  
Lin Zhang ◽  
Shuai Jiang ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cross Linking ◽  
Myocardial Collagen ◽  
Collagen Cross Linking

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.

scholarly journals Tropoelastin production and tropoelastin messenger RNA activity. Relationship to copper and elastin cross-linking in chick aorta

1986 ◽  
Vol 237 (1) ◽  
pp. 17-23 ◽  
Author(s):  
D Tinker ◽  
J Geller ◽  
N Romero ◽  
C E Cross ◽  
R B Rucker
Keyword(s):  
Messenger Rna ◽  
Copper Deficiency ◽  
Degradation Products ◽  
Lysyl Oxidase ◽  
Proteolytic Processing ◽  
Cross Linking ◽  
Cross Link ◽  
Dietary Copper ◽  
Lysine Residues ◽  
Link Formation

The elastin content of the chick thoracic aorta increases 2--3-fold during the first 3 weeks post-hatching. The deposition of elastin requires the covalent cross-linking of tropoelastin by means of lysine-derived cross-links. This process is sensitive to dietary copper intake, since copper serves as cofactor for lysyl oxidase, the enzyme that catalyses the oxidative deamination of the lysine residues involved in cross-link formation. Disruption of cross-linking alters tissue concentrations of both elastin and tropoelastin and results in a net decrease in aortic elastin content. Autoregulation of tropoelastin synthesis by changes in the pool sizes of elastin or tropoelastin has been suggested as a possible mechanism for the diminished aortic elastin content. Consequently, dietary copper deficiency was induced to study the effect of impaired elastin cross-link formation on tropoelastin synthesis. Elastin in aortae from copper-deficient chicks was only two-thirds to one-half the amount measured in copper-supplemented chicks, whereas copper-deficient concentrations of tropoelastin in aorta were at least 5-fold higher than normal. In spite of these changes, however, increased amounts of tropoelastin, copper deficiency and decreased amounts of elastin did not influence the amounts of functional elastin mRNA in aorta. Likewise, the production of tropoelastin in aorta explants was the same whether the explants were taken from copper-sufficient or -deficient birds. The lower accumulation of elastin in aorta from copper-deficient chicks appeared to be due to extracellular proteolysis, rather than to a decrease in the rate of synthesis. Electrophoresis of aorta extracts, followed by immunological detection of tropoelastin-derived products, indicated degradation products in aortae from copper-deficient birds. In extracts of aortae from copper-sufficient chicks, tropoelastin was not degraded and appeared to be incorporated into elastin without further proteolytic processing.

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.

Abstract MP166: PRKAR1A Deficiency Abrogates Cardiac Hypertrophy Through Inhibition of Mitochondrial Fission

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Yuening Liu ◽  
Peng Xia ◽  
Jingrui Chen ◽  
Patricia W Bandettini ◽  
Lawrence S Kirschner ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Postnatal Development ◽  
Contractile Function ◽  
Mitochondrial Fission ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Cardiac Complications ◽  
The Impact

Protein kinase A (PKA) is pivotal for cardiac function of human heart, and its dysregulation is involved with various cardiac pathologies. PKA regulatory subunit 1α (R1α, encoded by PRKAR1A gene) controls PKA kinase activity by sequestering the PKA catalytic subunits. Patients with PRKAR1A mutations are often diagnosed with Carney complex (CNC) and may die prematurely from cardiac complications such as heart failure. However, it remains unknown whether PRKAR1A deficiency interferes with normal heart growth during postnatal development. Here, we show that left ventricular mass is reduced in young CNC patients with PRKAR1A mutations or deletions. To investigate the impact of PRKAR1A deficiency on heart growth, we generated cardiac-specific PRKAR1A heterozygous knockout mice. Ablation of the PRKAR1A gene in mice increased cardiac PKA activity, reduced heart weight to body weight ratio and cardiomyocyte size without altering contractile function. Cardiomyocyte hypertrophy in response to activation of the α1-adrenergic receptor, was completely abolished by silencing of PRKAR1A . Mechanistically, depletion of PRKAR1A provoked PKA-dependent phosphorylation of the mitochondrial fission protein Drp1 at S637, resulting in impaired mitochondrial fission and diminished cardiomyocyte hypertrophy. In conclusion, PRKAR1A deficiency abrogates cardiac hypertrophy during postnatal development, likely through inhibiting Drp1-mediated mitochondrial fission. Our study provides novel mechanistic insights regarding the cardiac mortality associated with CNC.

scholarly journals Protective Effects of Thyroid Hormone Deprivation on Progression of Maladaptive Cardiac Hypertrophy and Heart Failure

2021 ◽  
Vol 8 ◽  
Author(s):  
Helena Kerp ◽  
Georg Sebastian Hönes ◽  
Elen Tolstik ◽  
Judith Hönes-Wendland ◽  
Janina Gassen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Heart Function ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Cardiovascular Morbidity And Mortality ◽  
The Impact

Purpose: Thyroid hormones (TH) play a central role for cardiac function. TH influence heart rate and cardiac contractility, and altered thyroid function is associated with increased cardiovascular morbidity and mortality. The precise role of TH in onset and progression of heart failure still requires clarification.Methods: Chronic left ventricular pressure overload was induced in mouse hearts by transverse aortic constriction (TAC). One week after TAC, alteration of TH status was induced and the impact on cardiac disease progression was studied longitudinally over 4 weeks in mice with hypo- or hyperthyroidism and was compared to euthyroid TAC controls. Serial assessment was performed for heart function (2D M-mode echocardiography), heart morphology (weight, fibrosis, and cardiomyocyte cross-sectional area), and molecular changes in heart tissues (TH target gene expression, apoptosis, and mTOR activation) at 2 and 4 weeks.Results: In diseased heart, subsequent TH restriction stopped progression of maladaptive cardiac hypertrophy and improved cardiac function. In contrast and compared to euthyroid TAC controls, increased TH availability after TAC propelled maladaptive cardiac growth and development of heart failure. This was accompanied by a rise in cardiomyocyte apoptosis and mTOR pathway activation.Conclusion: This study shows, for the first time, a protective effect of TH deprivation against progression of pathological cardiac hypertrophy and development of congestive heart failure in mice with left ventricular pressure overload. Whether this also applies to the human situation needs to be determined in clinical studies and would infer a critical re-thinking of management of TH status in patients with hypertensive heart disease.

scholarly journals Factors influencing haze formation and corneal flattening, and the impact of haze on visual acuity after conventional collagen cross-linking: a 12-month retrospective study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Anita Csorba ◽  
Kinga Kránitz ◽  
Péter Dormán ◽  
Andrea Popper-Sachetti ◽  
Huba Kiss ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Rank Test ◽  
Cross Linking ◽  
Grey Scale ◽  
Scale Unit ◽  
Haze Formation ◽  
Post Hoc ◽  
The Impact ◽  
Collagen Cross Linking ◽  
Corneal Flattening

Abstract Background Our aim was to determine associations of pachymetry, keratometry, and their changes with haze formation and corneal flattening after collagen cross-linking, and to analyse the relationship between postoperative haze and visual outcome. Methods Retrospective analysis was performed on 47 eyes of 47 patients with keratoconus using the Pentacam HR Scheimpflug camera before and 1, 3, 6 and 12 months after cross-linking. Corneal backscattered light values in grey scale unit were recorded in the anterior, center and posterior corneal layers and in four concentric rings. Surface area- and thickness-corrected grey scale unit values were assessed with an additional calculation. Friedman test with post hoc Wilcoxon signed-rank test was used to analyse changes in visual acuity, pachymetry, keratometry and densitometry. Spearman’s rank correlation test was used to detect correlations of haze formation and corneal flattening with pachymetry, keratometry and their postoperative change. Generalized estimating equations analysis was used to investigate the influence of densitometry values on postoperative visual acuity after controlling for the effect of preoperative keratometry. Results One year after treatment, significant flattening was observed in maximum and mean keratometry readings (p < 0.001). Significantly increased densitometry values were observed in three central rings compared to baseline (post hoc p < 0.0125). According to receiver operating characteristic curve, densitometry value of the anterior layer of 0–2 mm ring was the most characteristic parameter of densitometry changes after cross-linking (area under the curve = 0.936). Changes in haze significantly correlated with preoperative maximum keratometry (R = 0.303, p = 0.038) and with the changes in maximum keratometry (R = -0.412, p = 0.004). Changes in maximum keratometry correlated with preoperative maximum keratometry (R = -0.302, p = 0.038). Postoperative haze had a significant impact on uncorrected and best corrected distance visual acuity (β coefficient = 0.006, p = 0.041 and β coefficient = 0.003, p = 0.039, respectively). Conclusions Our findings indicate that in more advanced keratoconus more significant corneal flattening effect parallel with haze formation can be observed after cross-linking. Despite significant reduction of keratometry, postoperative corneal haze may limit final visual acuity.

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