Abstract 17939: Lack of the Alpha-11 Integrin in the Heart is Associated With Progressive Diastolic Dysfunction, Myofibrillar Disarray and Impaired Cardiomyocyte Growth

BACKGROUND: Integrins, transmembrane receptors, play crucial roles in diverse cellular and developmental processes due to critical interactions with the extracellular matrix (ECM). During fetal development and towards adulthood, heart growth and function is suggested to depend on forming and remodeling the ECM and its connection to the myocyte. Currently however, the role of integrins in cardiovascular development (CVD) is poorly defined. Thus, we hypothesized that the α11 integrin (α11), which is expressed by fibroblasts and binds preferentially to type I collagen fibers, plays a vital role in CVD. METHODS: α11 KO and wildtype littermate mice (both n = 8) were examined at 4 weeks and 8 weeks of age. Animals underwent function assessments, including echocardiography and invasive pressure volume (PV) loop analysis, and structural examination via histological and electron microscopy (EM) analysis. RESULTS: At 4 weeks, heart weight (HW) and HW indexed to tibial length were decreased in α11 KO mice (P < 0.05), which were normalized at 8 weeks. Echocardiography revealed reduced end-diastolic area (EDA) at 4 weeks (P < 0.05). Despite normalization of EDA at 8 weeks, PV loop revealed impaired diastolic function as evidence by increased EDP, prolonged Tau and steeper EDPVR (all P < 0.05). No differences in HR or systolic parameters were evident. α11 KO mice also demonstrated structural changes. WGA staining revealed evidence of myofibrillar disarray. Connexin 43 and desmin staining showed increased Z-disk and intermediate filament clustering, respectively. LV myocyte size was also reduced (P < 0.05). Similarly, EM analysis showed reduced cardiomyocyte thickness and distance between end plates (both P < 0.05). CONCLUSION: Loss of α11 resulted in progressively worsening diastolic function that was associated with myofibrillar disarray and impaired cardiomyocyte growth. These findings suggest that α11 is required for the development of normal heart structure and function.

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Role of Host-Derived Proteinases in Dentine Caries and Erosion

Caries Research ◽

10.1159/000380885 ◽

2015 ◽

Vol 49 (Suppl. 1) ◽

pp. 30-37 ◽

Cited By ~ 29

Author(s):

Marília Afonso Rabelo Buzalaf ◽

Senda Charone ◽

Leo Tjäderhane

Keyword(s):

Structural Changes ◽

Type I Collagen ◽

Organic Matrix ◽

Collagen Matrix ◽

Type I ◽

Cysteine Cathepsins ◽

Gradual Loss ◽

Collagen Molecules ◽

And Function

Demineralization in dentinal caries and erosion exposes dentine organic matrix. This exposed matrix, containing type I collagen and non-collagenous proteins, is then degraded by host collagenolytic enzymes, matrix metalloproteinases (MMPs) and cysteine cathepsins. The knowledge of the identities and function of these enzymes in dentine has accumulated only within the last 15 years, but has already formed a field of research called ‘dentine degradomics'. This research has demonstrated the role of endogenous collagenolytic enzymes in caries and erosion development. In demineralized dentine, the enzymes degrade triple-helical collagen molecules, leading to the gradual loss of collagen matrix. Even before that, they can cleave off the terminal non-helical ends of collagen molecules called telopeptides, leading to the structural changes at the intramolecular gap areas, which may affect or even prevent intrafibrillar remineralization, which is considered essential in restoring the dentine's mechanical properties. They may also cause the loss of non-collagenous proteins that could serve as nucleation sites for remineralization. Here we review the findings demonstrating that inhibition of salivary or dentine endogenous MMPs and cysteine cathepsins may provide preventive means against the progression of caries or erosion. Furthermore, we also suggest the future directions for the new experimental preventive research to gain more knowledge of the enzymes and their function during and after dentine demineralization, and the pathways to find the clinically acceptable means to prevent the functional activity of these enzymes.

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Collagen-the Ultrastructural Element of the Bone Matrix

Revista de Chimie ◽

10.37358/rc.18.7.6400 ◽

2018 ◽

Vol 69 (7) ◽

pp. 1706-1709

Author(s):

Nicoleta Dumitru ◽

Andra Cocolos ◽

Andra Caragheorgheopol ◽

Constantin Dumitrache ◽

Ovidiu Gabriel Bratu ◽

...

Keyword(s):

Type I Collagen ◽

Bone Microarchitecture ◽

Complex Structure ◽

Bone Matrix ◽

Organic Matrix ◽

Bone Diseases ◽

Bone Collagen ◽

Type I ◽

New Therapeutic Approaches ◽

And Function

There is an increased interest and more studies highlight the fact that bone strength depends not only on bone tissue quantity, but also on its quality, which is characterized by the geometry and shape of bones, trabecular bone microarchitecture, mineral content, organic matrix and bone turnover. Fibrillar type I collagen is the major organic component of bone matrix, providing form and a stable template for mineralization. The biomedical importance of collagen as a biomaterial for medical and cosmetic purposes and the improvement of the molecular, cellular biology and analytical technologies, led to increasing interest in establishing the structure of this protein and in setting of the relationships between sequence, structure, and function. Bone collagen crosslinking chemistry and its molecular packing structure are considered to be distinct features. This unique post-translational modifications provide to the fibrillar collagen matrices properties such as tensile strength and viscoelasticity. Understanding the complex structure of bone type I collagen as well as the dynamic nature of bone tissues will help to manage new therapeutic approaches to bone diseases.

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EFFECT OF COLLAGEN I GEL ON APOPTOSIS OF RAT HEPATIC STELLATE CELLS

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2014.27 ◽

2013 ◽

Vol 56 (2) ◽

pp. 73-79

Author(s):

Lenka Bittnerová ◽

Alena Jiroutová ◽

Emil Rudolf ◽

Martina Řezáčová ◽

Jiří Kanta

Keyword(s):

Hepatic Stellate Cells ◽

Type I Collagen ◽

Collagen Gel ◽

Stellate Cells ◽

Type I ◽

Function Type ◽

Fibrotic Liver ◽

Normal Rat ◽

And Function

Activated hepatic stellate cells (HSC) are a major source of fibrous proteins in cirrhotic liver. Inducing or accelerating their apoptosis is a potential way of liver fibrosis treatment. Extracellular matrix (ECM) surrounding cells in tissue affects their differentiation, migration, proliferation and function. Type I collagen is the main ECM component in fibrotic liver. We have examined how this protein modifies apoptosis of normal rat HSC induced by gliotoxin, cycloheximide and cytochalasin D in vitro and spontaneous apoptosis of HSC isolated from CCl4-damaged liver. We have found that type I collagen gel enhances HSC apoptosis regardless of the agent triggering this process.

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Type I Collagen-Mediated Changes in Gene Expression and Function of Prostate Cancer Cells

Cancer Treatment and Research - The Biology of Skeletal Metastases ◽

10.1007/978-1-4419-9129-4_5 ◽

2004 ◽

pp. 101-124 ◽

Cited By ~ 14

Author(s):

Jeffrey Kiefer ◽

Angela Alexander ◽

Mary C. Farach-Carson

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Cancer Cells ◽

Type I Collagen ◽

Type I ◽

Prostate Cancer Cells ◽

And Function

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Role of matrix metalloprotease-9 in hyperoxic injury in developing lung

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00441.2007 ◽

2008 ◽

Vol 295 (4) ◽

pp. L584-L592 ◽

Cited By ~ 45

Author(s):

Anne Chetty ◽

Gong-Jie Cao ◽

Mariano Severgnini ◽

Amy Simon ◽

Rod Warburton ◽

...

Keyword(s):

Lung Injury ◽

Structural Changes ◽

Type I Collagen ◽

Alveolar Epithelium ◽

Mouse Lung ◽

Type I ◽

Matrix Metalloprotease ◽

Oxidant Injury ◽

Hyperoxia Exposure

Matrix metalloprotease-9 (MMP-9) is increased in lung injury following hyperoxia exposure in neonatal mice, in association with impaired alveolar development. We studied the role of MMP-9 in the mechanism of hyperoxia-induced functional and histological changes in neonatal mouse lung. Reduced alveolarization with remodeling of ECM is a major morbidity component of oxidant injury in developing lung. MMP-9 mediates oxidant injury in developing lung causing altered lung remodeling. Five-day-old neonatal wild-type (WT) and MMP-9 (−/−) mice were exposed to hyperoxia for 8 days. The lungs were inflation fixed, and sections were examined for morphometry. The mean linear intercept and alveolar counts were evaluated. Immunohistochemistry for MMP-9 and elastin was performed. MMP-2, MMP-9, type I collagen, and tropoelastin were measured by Western blot analysis. Lung quasistatic compliance was studied in anaesthetized mice. MMP-2 and MMP-9 were significantly increased in lungs of WT mice exposed to hyperoxia compared with controls. Immunohistochemistry showed an increase in MMP-9 in mesenchyme and alveolar epithelium of hyperoxic lungs. The lungs of hyperoxia-exposed WT mice had less gas exchange surface area and were less compliant compared with room air-exposed WT and hyperoxia-exposed MMP-9 (−/−) mice. Type I collagen and tropoelastin were increased in hyperoxia-exposed WT with aberrant elastin staining. These changes were ameliorated in hyperoxia-exposed MMP-9 (−/−) mice. MMP-9 plays an important role in the structural changes consequent to oxygen-induced lung injury. Blocking MMP-9 activity may lead to novel therapeutic approaches in preventing bronchopulmonary dysplasia.

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Hydroxyl radical induced structural changes of collagen

Spectroscopy An International Journal ◽

10.1155/2007/496174 ◽

2007 ◽

Vol 21 (2) ◽

pp. 91-103 ◽

Cited By ~ 6

Author(s):

Helan Xiao ◽

Guoping Cai ◽

Mingyao Liu

Keyword(s):

Free Radical ◽

Hydroxyl Radicals ◽

Structural Changes ◽

Type I Collagen ◽

Free Radical Scavenger ◽

Radical Scavenger ◽

Type I ◽

Dependent Manner ◽

First Time

Extracellular matrix (ECM) plays an important role in cell differentiation, growth, migration and apoptosis. Collagen is the most abundant protein familyin vivo, but its function has still not been clearly defined yet. Reactive oxygen species (ROS) have a central role in oxidative cell stress. Electron spin resonance (ESR) spectroscopy indicates that type I collagen could uniquely scavenge hydroxyl radicals in dose- and time-dependent manner; whereas BSA and gelatin (a denatured collagen) have no such an effect. However, the mechanism by which type I collagen scavenges hydroxyl radicals is different from that of GSH, a well-known free radical scavenger. Using a new method, two-dimensional FTIR correlation analysis, for the first time, we show that the order of functional group changes of type I collagen in this process is amide I earlier than amide II than amide III than –CH– thanν(C=O). The results indicates that the structure of the main chain of collagen changed first, followed by more residue groupν(C=O) exposed to hydroxyl radicals. The reaction with the carbonyl group in collagen causes the hydroxyl free radicals to be scavenged. Therefore, ECM can effectively scavenge ROS under normal physiological conditions. When the proteins of ECM were denatured in the same way as gelatin, they lost their function as a free radical scavenger. All of these results provide new insight into therapy or prevention of oxidative stress, apoptosis and ageing.

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Discoidin Domain Receptor 1 Protein Is a Novel Modulator of Megakaryocyte-Collagen Interactions

Journal of Biological Chemistry ◽

10.1074/jbc.m112.431528 ◽

2013 ◽

Vol 288 (23) ◽

pp. 16738-16746 ◽

Cited By ~ 29

Author(s):

Vittorio Abbonante ◽

Cristian Gruppi ◽

Diana Rubel ◽

Oliver Gross ◽

Remigio Moratti ◽

...

Keyword(s):

Type I Collagen ◽

Type I ◽

Discoidin Domain Receptor ◽

Glycoprotein Vi ◽

Protein Levels ◽

Collagen Receptors ◽

And Function ◽

Extracellular Matrix Receptors ◽

Collagen Receptor ◽

Discoidin Domain Receptor 1

Growing evidence demonstrates that extracellular matrices regulate many aspects of megakaryocyte (MK) development; however, among the different extracellular matrix receptors, integrin α2β1 and glycoprotein VI are the only collagen receptors studied in platelets and MKs. In this study, we demonstrate the expression of the novel collagen receptor discoidin domain receptor 1 (DDR1) by human MKs at both mRNA and protein levels and provide evidence of DDR1 involvement in the regulation of MK motility on type I collagen through a mechanism based on the activity of SHP1 phosphatase and spleen tyrosine kinase (Syk). Specifically, we demonstrated that inhibition of DDR1 binding to type I collagen, preserving the engagement of the other collagen receptors, glycoprotein VI, α2β1, and LAIR-1, determines a decrease in MK migration due to the reduction in SHP1 phosphatase activity and consequent increase in the phosphorylation level of its main substrate Syk. Consistently, inhibition of Syk activity restored MK migration on type I collagen. In conclusion, we report the expression and function of a novel collagen receptor on human MKs, and we point out that an increasing level of complexity is necessary to better understand MK-collagen interactions in the bone marrow environment.

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Type I collagen gene regulation and the molecular pathogenesis of cirrhosis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1993.264.4.g589 ◽

1993 ◽

Vol 264 (4) ◽

pp. G589-G595 ◽

Cited By ~ 4

Author(s):

D. A. Brenner ◽

J. Westwick ◽

M. Breindl

Keyword(s):

Protein Interactions ◽

Type I Collagen ◽

Collagen Type ◽

Collagen Type I ◽

Molecular Pathogenesis ◽

Matrix Proteins ◽

Type I ◽

And Function ◽

Collagen Genes ◽

Insight Into

Cirrhosis is characterized by an increased deposition of extracellular matrix proteins, including type I collagen. Type I collagen is a product of two genes, alpha 1(I) and alpha 2(I), which are generally coordinately regulated. Since expression of type I collagen genes is increased during cirrhosis, understanding the structure and function of the regulatory components of the type I collagen genes should provide insight into the molecular pathogenesis of cirrhosis. This review will analyze the collagen alpha 1(I) gene with respect to chromatin structure, DNA methylation, regulation by agonists, and DNA-protein interactions.

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Influence of Decorin and Biglycan on Mechanical Properties of Multiple Tendons in Knockout Mice

Journal of Biomechanical Engineering ◽

10.1115/1.1835363 ◽

2005 ◽

Vol 127 (1) ◽

pp. 181-185 ◽

Cited By ~ 122

Author(s):

Paul S. Robinson ◽

Tung-Fu Huang ◽

Elan Kazam ◽

Renato V. Iozzo ◽

David E. Birk ◽

...

Keyword(s):

Mechanical Properties ◽

Type I Collagen ◽

Specific Treatment ◽

Treatment Modalities ◽

Type I ◽

Tail Tendon ◽

And Function ◽

Flexor Digitorum ◽

In Vivo Loading

Evaluations of tendon mechanical behavior based on biochemical and structural arrangement have implications for designing tendon specific treatment modalities or replacement strategies. In addition to the well studied type I collagen, other important constituents of tendon are the small proteoglycans (PGs). PGs have been shown to vary in concentration within differently loaded areas of tendon, implicating them in specific tendon function. This study measured the mechanical properties of multiple tendon tissues from normal mice and from mice with knock-outs of the PGs decorin or biglycan. Tail tendon fascicles, patellar tendons (PT), and flexor digitorum longus tendons (FDL), three tissues representing different in vivo loading environments, were characterized from the three groups of mice. It was hypothesized that the absence of decorin or biglycan would have individual effects on each type of tendon tissue. Surprisingly, no change in mechanical properties was observed for the tail tendon fascicles due to the PG knockouts. The loss of decorin affected the PT, causing an increase in modulus and stress relaxation, but had little effect on the FDL. Conversely, the loss of biglycan did not significantly affect the PT, but caused a reduction in both the maximum stress and modulus of the FDL. These results give mechanical support to previous biochemical data that tendons likely are uniquely tailored to their specific location and function. Variances such as those presented here need to be further characterized and taken into account when designing therapies or replacements for any one particular tendon.

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