Myofibroblast Phenotype and Reversibility of Fibrosis in Patients With End-Stage Heart Failure

Nagaraju, Chandan K.; Robinson, Emma; Abdesselem, Mouna; Trenson, Sander; Dries, Eef; Gilbert, Guillaume; Janssens, Stefan; Cleemput, Johan Van; Rega, Filip; Meyns, Bart; Roderick, H. Llewelyn; Driesen, Ronald B.; Sipido, Karin R.

doi:10.1016/j.jacc.2019.02.049

Cited by 123 publications

(93 citation statements)

References 44 publications

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“…Since OPN up-regulates LOX in human fibroblasts in culture, the authors proposed that the OPN-LOX axis might promote an exacerbated deposition of insoluble collagen (stiffer and more resistant to degradation) and the consequent alteration of LV function in these patients [52]. The increase of LOX and OPN levels, as well as those of TGF-β1 and periostin, in cardiac tissues from patients with end-stage HF has been confirmed in subsequent studies [53]. Interestingly, recent research shows the relevance of LOX as a target of miRNAs that regulate cardiac function and fibrosis, in particular of miR-19b [54].…”

Section: Lox and Loxls In Dilated And Hypertrophic Cardiomyopathies Amentioning

confidence: 87%

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

Rodrı́guez

Martínez-González

2019

Cells

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Lysyl oxidase (LOX) proteins comprise a family of five copper-dependent enzymes (LOX and four LOX-like isoenzymes (LOXL1-4)) critical for extracellular matrix (ECM) homeostasis and remodeling. The primary role of LOX enzymes is to oxidize lysyl and hydroxylysyl residues from collagen and elastin chains into highly reactive aldehydes, which spontaneously react with surrounding amino groups and other aldehydes to form inter-and intra-catenary covalent cross-linkages. Therefore, they are essential for the synthesis of a mature ECM and assure matrix integrity. ECM modulates cellular phenotype and function, and strikingly influences the mechanical properties of tissues. This explains the critical role of these enzymes in tissue homeostasis, and in tissue repair and remodeling. Cardiac ECM is mainly composed of fibrillar collagens which form a complex network that provides structural and biochemical support to cardiac cells and regulates cell signaling pathways. It is now becoming apparent that cardiac performance is affected by the structure and composition of the ECM and that any disturbance of the ECM contributes to cardiac disease progression. This review article compiles the major findings on the contribution of the LOX family to the development and progression of myocardial disorders. part of the mechanoresponsive gene programs responsible for the mechanical regulation of gene expression in cardiac myocytes and fibroblasts [11]. Thus, LOX/LOXLs contribute to cardiac fibrosis, but are also active players involved in the cellular mechanisms underlying cardiac dysfunction and disease progression.In the last years, multiple studies have contributed to the understanding of the pathophysiological role of the LOX family in human diseases and, in particular, in the cardiovascular system. The involvement of this family on vascular diseases has been recently reviewed [12]. Further, LOX/LOXLs participate in a variety of processes affecting the heart, from those associated to post-myocardial infarction (MI) cardiac remodeling, cardiac hypertrophy triggered by pressure or volume overload, heart failure (HF) with preserved ejection fraction (HFPEF) associated with obesity and metabolic syndrome or atrial fibrillation. The strong impact of the alteration of LOX/LOXLs on CCL and heart function supports the interest of these family of enzymes as pharmacological targets to improve cardiac remodeling and slow the progression to HF. In this review article we focus on those findings that support the fundamental involvement of the LOX family in the mechanisms underlying cardiac damage and repair. The LOX Family of ECM-Modifying EnzymesLOX is an extracellular enzyme which governs the post-translational modification of ECM collagen and elastin. LOX catalyzes the oxidative deamination of specific ε-amino groups of lysine and hydroxylysine residues in collagen and elastin. This leads to the generation of highly reactive peptidyl α-aminoadipic γ-semialdehydes and the release of hydrogen peroxide as by-product [1-3] (Figure 1). This reactio...

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Section: Lox and Loxls In Dilated And Hypertrophic Cardiomyopathies Amentioning

confidence: 87%

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

Rodrı́guez

Martínez-González

2019

Cells

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“…As such, the prevention or reversal of pathological fibrotic remodeling has been a research target for numerous years and has led to a wealth of studies aimed in uncovering the mechanistic basis for cardiac fibrosis. Recently, studies using isolated myofibroblasts from HF patients have suggested the possibility of reversing fibrosis by inhibition of TGFβ receptor signaling (Frangogiannis, 2019b;Nagaraju et al, 2019). These findings provide support to reason the idea of myofibroblasts returning to quiescent fibroblast states (Nagaraju et al, 2019).…”

Section: Discussionmentioning

confidence: 60%

“…Recently, studies using isolated myofibroblasts from HF patients have suggested the possibility of reversing fibrosis by inhibition of TGFβ receptor signaling (Frangogiannis, 2019b;Nagaraju et al, 2019). These findings provide support to reason the idea of myofibroblasts returning to quiescent fibroblast states (Nagaraju et al, 2019). However, translating these findings in vivo will require consideration of numerous other factors which influence cardiac fibrosis.…”

Section: Discussionmentioning

confidence: 87%

Leukocyte-Dependent Regulation of Cardiac Fibrosis

Okyere

Tilley

2020

Front. Physiol.

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Cardiac fibrosis begins as an intrinsic response to injury or ageing that functions to preserve the tissue from further damage. Fibrosis results from activated cardiac myofibroblasts, which secrete extracellular matrix (ECM) proteins in an effort to replace damaged tissue; however, excessive ECM deposition leads to pathological fibrotic remodeling. At this extent, fibrosis gravely disturbs myocardial compliance, and ultimately leads to adverse outcomes like heart failure with heightened mortality. As such, understanding the complexity behind fibrotic remodeling has been a focal point of cardiac research in recent years. Resident cardiac fibroblasts and activated myofibroblasts have been proven integral to the fibrotic response; however, several findings point to additional cell types that may contribute to the development of pathological fibrosis. For one, leukocytes expand in number after injury and exhibit high plasticity, thus their distinct role(s) in cardiac fibrosis is an ongoing and controversial field of study. This review summarizes current findings, focusing on both direct and indirect leukocyte-mediated mechanisms of fibrosis, which may provide novel targeted strategies against fibrotic remodeling.

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“…In the disease course of heart failure after MI, the passive stiffness of the overall myocardium becomes collagen dependent, which is closely related to the collagen content and shows that the proinflammatory and profibrosis signal plays an important role in this process [12]. In this study, the changes in collagen volume after MI in rats were observed by Masson staining.…”

Section: Effects Of Wenxin Granules On Collagen Volume Of Myocardial mentioning

confidence: 70%

Wenxin Granules Influence the TGFβ-P38/JNK MAPK Signaling Pathway and Attenuate the Collagen Deposition in the Left Ventricle of Myocardial Infarction Rats

Lou

et al. 2019

Cardiology Research and Practice

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Background. A large number of proinflammatory/anti-inflammatory cytokines are produced in the extracellular matrix (ECM) after myocardial infarction (MI), and the inflammatory pathways activated by these inflammatory stimuli are involved in the regulation of lesions with excessive accumulation of ECM. Wenxin granules can play a protective role against MI, but the mechanism of its effect on the inflammatory pathway and ECM collagen expression is still unclear. Objective. To verify the effect of Wenxin granules on the inflammatory pathway and collagen expression after MI. Method. e proximal left anterior descending coronary artery in rats was ligated to induce acute MI. en, animals were randomly assigned to the model group, the Carvedilol group, and the Wenxin Granules group. In addition, sham operation rats were used as the control group. 10 rats were allocated in each group. Gavage was given once a day for 4 weeks. e changes of cardiac hemodynamics were detected by the catheter method, morphological changes were observed by HE staining, and myocardial tissue collagen volume was counted by Immunohistochemistry combined with Masson staining, and the expression of inflammatory TGFβ-p38/JNK MAPK signal pathway markers was detected by Western blot. Results. Wenxin granules could significantly improve the hemodynamics, so that the fibrosis scar was relatively dense and uniform, and the residual myocardium was relatively neat, while Collagen type I and III volume and TGFβ expression levels were lessened. Although there were no differences in the expression of CTGF, p38, and JNK proteins, their phosphorylation levels showed significant differences. Conclusion. Wenxin granules can affect the inflammationrelated TGFβ-p38/JNK MAPK signaling pathway and change the structural properties of myocardium and scar after MI by attenuated collagen deposition in the left ventricular myocardial tissue to improve cardiac function.

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Myofibroblast Phenotype and Reversibility of Fibrosis in Patients With End-Stage Heart Failure

Cited by 123 publications

References 44 publications

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

Leukocyte-Dependent Regulation of Cardiac Fibrosis

Wenxin Granules Influence the TGFβ-P38/JNK MAPK Signaling Pathway and Attenuate the Collagen Deposition in the Left Ventricle of Myocardial Infarction Rats

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