Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction

González-Santamaría, José; Villalba, María; Busnadiego, Óscar; López-Olañeta, Marina; Sandoval, Pilar; Snabel, Jessica; López–Cabrera, Manuel; Erler, Janine T.; Hanemaaijer, Roeland; Lara‐Pezzi, Enrique; Rodrı́guez-Pascual, Fernando

doi:10.1093/cvr/cvv214

Cited by 112 publications

(80 citation statements)

References 51 publications

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“…Type I collagen is further modified by LOX-catalyzed cross-linking. The expression of all four LOX isoforms is increased in the infarct area and in the border zone at 3–7 days post-MI (Gonzalez-Santamaria et al 2016). This correlates with significant accumulation of mature collagen fibers and extensive remodeling, and LOX inhibition with a pharmacological inhibitor or a neutralizing antibody reduces infarct expansion resulting in improved cardiac function at 28 days post-MI (Gonzalez-Santamaria et al 2016).…”

Section: Replacement Fibrosis After Mi: Phases and Repair Vs Remodelingmentioning

confidence: 99%

“…The expression of all four LOX isoforms is increased in the infarct area and in the border zone at 3–7 days post-MI (Gonzalez-Santamaria et al 2016). This correlates with significant accumulation of mature collagen fibers and extensive remodeling, and LOX inhibition with a pharmacological inhibitor or a neutralizing antibody reduces infarct expansion resulting in improved cardiac function at 28 days post-MI (Gonzalez-Santamaria et al 2016). Cross-linking of the collagen fibers leads to increased tensile strength and contraction of the scar, which alters the geometry of the chamber and contributes to remodeling in the remote areas of the ventricular wall (van den Borne et al 2010).…”

Section: Replacement Fibrosis After Mi: Phases and Repair Vs Remodelingmentioning

confidence: 99%

“…In vitro studies with murine and rat primary cardiac fibroblasts suggest that the anti-fibrotic mechanism of NRG1 is mediated through inhibition of TGF-β signaling and myofibroblast transdifferentiation. Other putative therapeutic strategies to inhibit pro-fibrotic signaling include LOX inhibition, Wnt inhibition, and histone deacetylase inhibition (Hermans et al 2012; Schuetze et al 2014; Gonzalez-Santamaria et al 2016). …”

Section: Concluding Remarks and Future Prospectsmentioning

confidence: 99%

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Cardiac fibrosis in myocardial infarction—from repair and remodeling to regeneration

2016

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Ischemic cell death during a myocardial infarction leads to a multiphase reparative response in which the damaged tissue is replaced with a fibrotic scar produced by fibroblasts and myofibroblasts. This also induces geometrical, biomechanical, and biochemical changes in the uninjured ventricular wall eliciting a reactive remodeling process that includes interstitial and perivascular fibrosis. Although the initial reparative fibrosis is crucial for preventing rupture of the ventricular wall, an exaggerated fibrotic response and reactive fibrosis outside the injured area are detrimental as they lead to progressive impairment of cardiac function and eventually to heart failure. In this review, we summarize current knowledge of the mechanisms of both reparative and reactive cardiac fibrosis in response to myocardial infarction, discuss the potential of inducing cardiac regeneration through direct reprogramming of fibroblasts and myofibroblasts into cardiomyocytes, and review the currently available and potential future therapeutic strategies to inhibit cardiac fibrosis.Graphical abstractReparative response following a myocardial infarction. Hypoxia-induced cardiomyocyte death leads to the activation of myofibroblasts and a reparative fibrotic response in the injured area. Right top In adult mammals, the fibrotic scar formed at the infarcted area is permanent and promotes reactive fibrosis in the uninjured myocardium. Right bottom In teleost fish and newts and in embryonic and neonatal mammals, the initial formation of a fibrotic scar is followed by regeneration of the cardiac muscle tissue. Induction of post-infarction cardiac regeneration in adult mammals is currently the target of intensive research and drug discovery attempts

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Section: Replacement Fibrosis After Mi: Phases and Repair Vs Remodelingmentioning

confidence: 99%

Section: Replacement Fibrosis After Mi: Phases and Repair Vs Remodelingmentioning

confidence: 99%

Section: Concluding Remarks and Future Prospectsmentioning

confidence: 99%

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Cardiac fibrosis in myocardial infarction—from repair and remodeling to regeneration

2016

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“…Concurrent with cell proliferation, activated scar fibroblasts produce lysyl oxidase (LOX) enzymes, which strengthen and stiffen the collagen network by crosslinking fibres [149]. Inhibition of LOX modulates collagen accumulation and maturation, and improves cardiac function in a model of murine infarct, suggesting that LOX family members are plausible targets for intervention [150, 151]. Additionally, targeting collagen fibre orientation can affect overall scar stiffness by making scars more (or less) isotropic [20, 152].…”

Section: Making Better Scars – Potential For Targeted Interventionsmentioning

confidence: 99%

The Living Scar – Cardiac Fibroblasts and the Injured Heart

Rog-Zielinska

Norris

Kohl

et al. 2016

Trends in Molecular Medicine

136

102

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Cardiac scars, often perceived as “dead” tissue, are very much alive, with heterocellular activity ensuring the maintenance of structural and mechanical integrity following heart injury. To form a scar, non-myocytes such as fibroblasts, proliferate and are recruited from intra- and extra-cardiac sources. Fibroblasts perform important autocrine and paracrine signalling functions. They also establish mechanical and, as is increasingly evident, electrical junctions with other cells. While fibroblasts were previously thought to act simply as electrical insulators, they may be electrically connected among themselves and, under certain circumstances, to other cells, including cardiomyocytes. A better understanding of these interactions will help target scar structure and function and facilitate the development of novel therapies aimed at modifying scar properties for patient benefit. This review explores available insight and recent concepts on fibroblast integration in the heart, and highlights potential avenues for harnessing their roles to optimise scar function following heart injury such as infarction, and therapeutic interventions such as ablation.

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“…Whereas, type III collagen is more extensible, weaker and immature than thick structural type I collagen; and the synthesis of type III collagen occur in response to injury [26], independent of LOX. Collagen tensile strength mainly relies on the cross-linking; and, it is considered that not only the content of collagen, but its cross-linking which has an impact on stiffness [27]. LOX gene expression was not altered in this study; however, the decrease in LOX protein expression is suggestive of alterations in post-translational modification.…”

Section: Discussionmentioning

confidence: 60%

Association of altered collagen content and lysyl oxidase expression in degenerative mitral valve disease

Purushothaman

Turnbull

et al. 2017

Cardiovascular Pathology

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Background Collagen cross-linking is mediated by lysyl oxidase (LOX) enzyme in the extracellular matrix (ECM) of mitral valve leaflets. Alterations in collagen content and LOX protein expression in the ECM of degenerative mitral valve may enhance leaflet expansion and disease severity. Methods Twenty posterior degenerative mitral valve leaflets from patients with severe mitral regurgitation were obtained at surgery. Five normal posterior mitral valve leaflets procured during autopsy served as controls. Valvular interstitial cells (VICs) density was quantified by immunohistochemistry, collagen types I and III by picro-sirius red staining and immunohistochemistry, and proteoglycans by alcian blue staining. Protein expression of LOX and its mediator TGFβ1 were quantified by immunofluorescence and gene expression by PCR. Results VICs density was increased, structural type I collagen density was reduced, while reparative type III collagen and proteoglycan densities were increased (p<0.0001) with an increase in spongiosa layer thickness in myxomatous valves. These changes were associated with a reduction in LOX (p<0.0001) and increase in TGFβ1 protein expression (p<0.0001). However, no significant change was seen in gene expression. Linear regression analysis identified a correlation between type I collagen density and LOX grade (R2=0.855; p<0.0001). Conclusions Reduced type I collagen density with a simultaneous increase in type III collagen and proteoglycan densities possibly contributes to spongiosa layer expansion resulting in incompetent mitral valve leaflets. Observed changes in type I and III collagen densities in DMVD may be secondary to alterations in LOX protein expression, contributing to disorganization of ECM and disease severity.

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Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction

Abstract: LOX family members contribute significantly to the detrimental effects of cardiac remodelling, highlighting LOX inhibition as a potential therapeutic strategy for post-infarction recovery.

Cited by 112 publications

References 51 publications

Cardiac fibrosis in myocardial infarction—from repair and remodeling to regeneration

Cardiac fibrosis in myocardial infarction—from repair and remodeling to regeneration

The Living Scar – Cardiac Fibroblasts and the Injured Heart

Association of altered collagen content and lysyl oxidase expression in degenerative mitral valve disease

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