Role of collagen turnover biomarkers in the noninvasive assessment of myocardial fibrosis: an update

The pro-fibrotic milieu, as the result of the extracellular matrix remodeling, is a central feature in the pathophysiology of heart disease and contributes to its high morbidity and mortality. Fibrosis is a recognized risk factor for development of heart failure and arrythmias and is usually detected by cardiac magnetic resonance or endomyocardial biopsy. Collagen type I and type III are major components of the collagen network, and the assessment of their derived biomarkers could serve as estimate of the myocardial fibrotic content. This review summarizes data from numerous studies in which these biomarkers have proven their diagnostic and prognostic utility, setting the stage for further randomized clinical trials that might translate into early implementation of antifibrotic therapies.

Download Full-text

Precision-Cut Kidney Slices as a Tool to Understand the Dynamics of Extracellular Matrix Remodeling in Renal Fibrosis

Biomarker Insights ◽

10.4137/bmi.s38439 ◽

2016 ◽

Vol 11 ◽

pp. BMI.S38439 ◽

Cited By ~ 7

Author(s):

Federica Genovese ◽

Zsolt S. Kàrpàti ◽

Signe H. Nielsen ◽

Morten A. Karsdal

Keyword(s):

Extracellular Matrix ◽

Collagen Type ◽

Interstitial Fibrosis ◽

Ex Vivo ◽

Collagen Type I ◽

Extracellular Matrix Remodeling ◽

Type I ◽

Matrix Remodeling ◽

Renal Interstitial Fibrosis ◽

Ex Vivo Model

The aim of this study was to set up an ex vivo model for renal interstitial fibrosis in order to investigate the extracellular matrix (ECM) turnover profile in the fibrotic kidney. We induced kidney fibrosis in fourteen 12-week-old male Sprague Dawley rats by unilateral ureteral obstruction (UUO) surgery of the right ureter. The left kidney (contralateral) was used as internal control. Six rats were sham operated and used as the control group. Rats were terminated two weeks after the surgery; the kidneys were excised and precision-cut kidney slices (PCKSs) were cultured for five days in serum-free medium. Markers of collagen type I formation (P1NP), collagen type I and III degradation (C1M and C3M), and α-smooth muscle actin (αSMA) were measured in the PCKS supernatants by enzyme-linked immunosorbent assay. P1NP, C1M, C3M, and α-SMA were increased up to 2- to 13-fold in supernatants of tissue slices from the UUO-ligated kidneys compared with the contralateral kidneys ( P < 0.001) and with the kidneys of sham-operated animals ( P < 0.0001). The markers could also reflect the level of fibrosis in different animals. The UUO PCKS ex vivo model provides a valuable translational tool for investigating the extracellular matrix remodeling associated with renal interstitial fibrosis.

Download Full-text

WNT-5A regulates TGF-β-related activities in liver fibrosis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00160.2016 ◽

2017 ◽

Vol 312 (3) ◽

pp. G219-G227 ◽

Cited By ~ 21

Author(s):

Leonie Beljaars ◽

Sara Daliri ◽

Christa Dijkhuizen ◽

Klaas Poelstra ◽

Reinoud Gosens

Keyword(s):

Liver Fibrosis ◽

Functional Role ◽

Collagen Type ◽

Collagen Type I ◽

Matrix Proteins ◽

Type I ◽

Human Livers

WNT-5A is a secreted growth factor that belongs to the noncanonical members of the Wingless-related MMTV-integration family. Previous studies pointed to a connection between WNT-5A and the fibrogenic factor TGF-β warranting further studies into the functional role of WNT-5A in liver fibrosis. Therefore, we studied WNT-5A expressions in mouse and human fibrotic livers and examined the relation between WNT-5A and various fibrosis-associated growth factors, cytokines, and extracellular matrix proteins. WNT-5A gene and protein expressions were significantly increased in fibrotic mouse and human livers compared with healthy livers. Regression or therapeutic intervention in mice resulted in decreased hepatic WNT-5A levels paralleled by lower collagen levels. Immunohistochemical analysis showed WNT-5A staining in fibrotic septa colocalizing with desmin staining indicating WNT-5A expression in myofibroblasts. In vitro studies confirmed WNT-5A expression in this cell type and showed that TGF-β significantly enhanced WNT-5A expression in contrast to PDGF-BB and proinflammatory cytokines IL-1β and TNF-α. Additionally, TGF-β induces the expression of the WNT receptors FZD2 and FZD8. After silencing of WNT-5A, reduced levels of collagen type I, vimentin, and fibronectin in TGF-β-stimulated myofibroblasts were measured compared with nonsilencing siRNA-treated controls. Interestingly, the antifibrotic cytokine IFNγ suppressed WNT-5A in vitro and in vivo. IFNγ-treated fibrotic mice showed significantly less WNT-5A expression compared with untreated fibrotic mice. In conclusion, WNT-5A paralleled collagen I levels in fibrotic mouse and human livers. WNT-5A expression in myofibroblasts is induced by the profibrotic factor TGF-β and plays an important role in TGF-β-induced regulation of fibrotic matrix proteins, whereas its expression can be reversed upon treatment, both in vitro and in vivo. NEW & NOTEWORTHY This study describes the localization and functional role of WNT-5A in human and mouse fibrotic livers. Hepatic WNT-5A expression parallels collagen type I expression. In vivo and in vitro, the myofibroblasts were identified as the key hepatic cells producing WNT-5A. WNT-5A is under control of TGF-β and its activities are primarily profibrotic.

Download Full-text

Role of catechin on collagen type I stability upon oxidation: a NMR approach

Natural Product Research ◽

10.1080/14786419.2019.1570509 ◽

2019 ◽

Vol 34 (1) ◽

pp. 53-62 ◽

Cited By ~ 4

Author(s):

Massimo Lucarini ◽

Fabio Sciubba ◽

Donatella Capitani ◽

Maria Enrica Di Cocco ◽

Laura D’Evoli ◽

...

Keyword(s):

Collagen Type ◽

Collagen Type I ◽

Type I

Download Full-text

Quantitative assessment of forward and backward second harmonic three dimensional images of collagen Type I matrix remodeling in a stimulated cellular environment

Journal of Structural Biology ◽

10.1016/j.jsb.2012.05.004 ◽

2012 ◽

Vol 180 (1) ◽

pp. 17-25 ◽

Cited By ~ 20

Author(s):

Thomas Abraham ◽

Damian Kayra ◽

Bruce McManus ◽

Alex Scott

Keyword(s):

Quantitative Assessment ◽

Collagen Type ◽

Second Harmonic ◽

Three Dimensional ◽

Collagen Type I ◽

Type I ◽

Matrix Remodeling ◽

Cellular Environment ◽

Three Dimensional Images

Download Full-text

Therapeutic Effects of Acupuncture through Enhancement of Functional Angiogenesis and Granulogenesis in Rat Wound Healing

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/464586 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

Sang In Park ◽

Yun-Young Sunwoo ◽

Yu Jin Jung ◽

Woo Chul Chang ◽

Moon-Seo Park ◽

...

Keyword(s):

Wound Healing ◽

Collagen Type ◽

Interleukin 1 ◽

Treated Group ◽

Collagen Type I ◽

Control Group ◽

Therapeutic Effects ◽

Type I ◽

Matrix Remodeling ◽

Cd 31

Acupuncture regulates inflammation process and growth factors by increasing blood circulation in affected areas. In this study, we examined whether acupuncture has an effect on wound healing in injured rat. Rats were assigned randomly into two groups: control group and acupuncture group. Acupuncture treatment was carried out at 8 sites around the wounded area. We analyzed the wound area, inflammatory cytokines, proliferation of resident cells, and angiogenesis and induction of extracelluar matrix remodeling. At 7 days after-wounding the wound size in acupuncture-treat group was decreased more significantly compared to control group. In addition, the protein levels of proinflammatory cytokines such as tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) were significantly decreased compared to the control at 2 and 7 days post-wounding. Also, we analyzed newly generated cells by performing immunostaining for PCNA and using several phenotype markers such as CD-31,α-SMA, and collagen type I. In acupuncture-treated group, PCNA-positive cell was increased and PCNA labeled CD-31-positive vessels,α-SMA- and collagen type I-positive fibroblastic cells, were increased compared to the control group at 7 days post-wounding. These results suggest that acupuncture may improve wound healing through decreasing pro-inflammatory response, increasing cell proliferation and angiogenesis, and inducing extracellular matrix remodeling.

Download Full-text

Blockade of hypoxia-reoxygenation-mediated collagen type I expression and MMP activity by overexpression of TGF-β1delivered by AAV in mouse cardiomyocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00488.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. H1833-H1838 ◽

Cited By ~ 21

Author(s):

Chang-Ping Hu ◽

Abhijit Dandapat ◽

Yong Liu ◽

Paul L. Hermonat ◽

Jawahar L. Mehta

Keyword(s):

Cardiac Remodeling ◽

Collagen Type ◽

Transforming Growth Factor ◽

Collagen Type I ◽

Type I ◽

Antioxidant Mechanism ◽

Multifunctional Peptides ◽

Expression And Activity ◽

Hypoxia Reoxygenation

Transforming growth factor (TGF)-β1is one of the most pleiotropic and multifunctional peptides known. While the cardioprotective effect of TGF-β1during ischemia is well known, the specific role of TGF-β1in altering the cardiac remodeling process remains unclear. This study was designed to examine the regulation of hypoxia-reoxygenation-mediated collagen type I expression and activity of matrix metalloproteinases (MMPs) by overexpression of TGF-β1in cultured HL-1 mouse cardiomyocytes. TGF-β1was overexpressed in cardiomyocytes by transfection with adeno-associated virus (AAV)/TGF-β1Latentor with AAV/TGF-β1ACT(active TGF-β1). Twenty-four hours of hypoxia followed by 3 h of reoxygenation (H-R) markedly enhanced (pro)collagen type I expression and activity of MMPs concomitant with an increase in reactive oxygen species (ROS) release and LOX-1 expression. Overexpression of TGF-β1reduced these alterations induced by H-R. TGF-β1overexpression also blocked H-R-mediated p38 and p44/42 MAPK activation. Transfection with AAV/TGF-β1ACTwas superior to that with AAV/TGF-β1Latent. These data for the first time demonstrate that H-R induces signals for cardiac remodeling in cardiomyocytes and TGF-β1can modulate, possibly via antioxidant mechanism, these signals. These findings contribute to further understanding of the role of TGF-β1in the cardiac remodeling process.

Download Full-text

The role of collagen type I α2 polymorphisms: intracranial aneurysms in Koreans

Surgical Neurology ◽

10.1016/j.surneu.2009.02.009 ◽

2009 ◽

Vol 72 (1) ◽

pp. 48-53 ◽

Cited By ~ 8

Author(s):

Sung-Pil Joo ◽

Tae-Sun Kim ◽

Il-Kwon Lee ◽

Jung-Kil Lee ◽

Bo-Ra Seo ◽

...

Keyword(s):

Intracranial Aneurysms ◽

Collagen Type ◽

Collagen Type I ◽

Type I

Download Full-text

Discoidin Domain Receptor 2 regulates AT1 receptor expression in Angiotensin II-stimulated cardiac fibroblasts via fibronectin-dependent Integrin-β1 signalling

10.1101/2021.05.06.442987 ◽

2021 ◽

Author(s):

Allen Sam Titus ◽

Harikrishnan V ◽

Mingyi Wang ◽

Edward G Lakkatta ◽

Shivakumar Kailasam

Keyword(s):

Angiotensin Ii ◽

Collagen Type ◽

Cardiac Fibroblasts ◽

Collagen Type I ◽

Cardiac Fibroblast ◽

Regulatory Role ◽

Type I ◽

Integrin Β1 ◽

Fibronectin Expression

Fibronectin is an extracellular matrix glycoprotein with a regulatory role in fundamental cellular processes. Recent reports on the cardioprotective effect of fibronectin inhibition in a setting of myocardial injury suggest a role for fibronectin in cardiac fibroblast function, which remains largely unexplored. This study probed the molecular basis and functional implications of fibronectin gene expression in cardiac fibroblasts exposed to Angiotensin II, a potent pro-fibrotic factor in the myocardium. Using gene knockdown and over-expression approaches, western blotting and promoter pull-down assay, we show that collagen type I-activated Discoidin Domain Receptor 2 (DDR2) mediates Angiotensin II-stimulated transcriptional up-regulation of fibronectin expression by Yes-activated Protein in cardiac fibroblasts. Further, siRNA-mediated fibronectin knockdown attenuated Angiotensin II-dependent expression of anti-apoptotic cIAP2 and promoted cell death under oxidative stress. Fibronectin was also found to mediate Angiotensin II-stimulated collagen type I expression. Importantly, an obligate role for fibronectin was observed in Angiotensin II-stimulated expression of its receptor, AT1R, which would link ECM signalling and Angiotensin II signalling in cardiac fibroblasts. Moreover, the regulatory role of DDR2-dependent fibronectin expression in Ang II-stimulated cIAP2, collagen type I and AT1R expression was mediated by Integrin-β1-integrin-linked kinase signalling. The pro-survival role of fibronectin in cardiac fibroblasts and its regulatory role in collagen and AT1R expression, downstream of DDR2, could be critical determinants of cardiac fibroblast-mediated wound healing following myocardial injury. Our findings point to a complex mechanism of regulation of cardiac fibroblast function involving two major extracellular matrix proteins, collagen type I and fibronectin, and their receptors, DDR2 and Integrin-β1.

Download Full-text