Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Santos, Gabriela Leão; Hartmann, Svenja; Zimmermann, Wolfram H.; Ridley, Anne J.; Lutz, Susanne

doi:10.1016/j.yjmcc.2019.06.015

Cited by 32 publications

(18 citation statements)

References 79 publications

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“…In this context, the inhibitory effect of ROCK inhibitors on stiffness was mediated by the regulation of lysyl oxidase, the collagen cross-linking enzyme and involved the activation of the actin-dependent MRTF/SRF pathway. This study also showed, that ROCK inhibitors similarly decreased stiffness of human engineered connective tissue and rat engineered cardiac muscle (Santos et al, 2019).…”

Section: Consequences Of Stiffness Changes On Cardiomyocyte Performancesupporting

confidence: 69%

“…Santos et al utilized rat ring-shaped engineered connective tissue comprised of cardiac fibroblasts and collagen I while using ROCK signaling inhibitors. This resulted in reduced tissue stiffness, and also reduced TGF-β signaling-driven tissue stiffening (Santos et al, 2019). In this context, the inhibitory effect of ROCK inhibitors on stiffness was mediated by the regulation of lysyl oxidase, the collagen cross-linking enzyme and involved the activation of the actin-dependent MRTF/SRF pathway.…”

Section: Consequences Of Stiffness Changes On Cardiomyocyte Performancementioning

confidence: 99%

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Sensing and Responding of Cardiomyocytes to Changes of Tissue Stiffness in the Diseased Heart

Münch

Abdelilah‐Seyfried

2021

Front. Cell Dev. Biol.

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Cardiomyocytes are permanently exposed to mechanical stimulation due to cardiac contractility. Passive myocardial stiffness is a crucial factor, which defines the physiological ventricular compliance and volume of diastolic filling with blood. Heart diseases often present with increased myocardial stiffness, for instance when fibrotic changes modify the composition of the cardiac extracellular matrix (ECM). Consequently, the ventricle loses its compliance, and the diastolic blood volume is reduced. Recent advances in the field of cardiac mechanobiology revealed that disease-related environmental stiffness changes cause severe alterations in cardiomyocyte cellular behavior and function. Here, we review the molecular mechanotransduction pathways that enable cardiomyocytes to sense stiffness changes and translate those into an altered gene expression. We will also summarize current knowledge about when myocardial stiffness increases in the diseased heart. Sophisticated in vitro studies revealed functional changes, when cardiomyocytes faced a stiffer matrix. Finally, we will highlight recent studies that described modulations of cardiac stiffness and thus myocardial performance in vivo. Mechanobiology research is just at the cusp of systematic investigations related to mechanical changes in the diseased heart but what is known already makes way for new therapeutic approaches in regenerative biology.

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Section: Consequences Of Stiffness Changes On Cardiomyocyte Performancesupporting

confidence: 69%

Section: Consequences Of Stiffness Changes On Cardiomyocyte Performancementioning

confidence: 99%

Sensing and Responding of Cardiomyocytes to Changes of Tissue Stiffness in the Diseased Heart

Münch

Abdelilah‐Seyfried

2021

Front. Cell Dev. Biol.

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“…Fasudil, a selective inhibitor for the RhoA-ROCK pathway, has been used in clinic as a vasodilator [18,19,20] and for RhoA-mediated functional studies [21,22,23]. We previously reported that fasudil can partially block Th2 differentiation and OVA-induced allergic airway inflammation [27].…”

Section: Discussionmentioning

confidence: 99%

“…It is also applied in patients with pulmonary hypertension [19], diabetic patients with left ventricular diastolic dysfunction [20], etc. For RhoA functional research, fasudil has been applied for fibrosis therapy in several models [21,22,23]. Fasudil may also inhibit Th17 cells.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Rho-Kinase Downregulates Th17 Cells and Ameliorates Hepatic Fibrosis by Schistosoma japonicum Infection

Zhou

Yang

Mei

et al. 2019

Cells

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Background: Schistosomiasis is an immunopathogenic disease in which Th17 cells play vital roles. Hepatic granuloma formation and subsequent fibrosis are its main pathologic manifestations and the leading causes of hepatic cirrhosis, and effective therapeutic interventions are lacking. In this study, we explored the effects of fasudil, a selective RhoA–Rho-associated kinase (ROCK) inhibitor, on Th17 cells and the pathogenesis of schistosomiasis. Methods: Mice were infected with Schistosoma japonicum and treated with fasudil. The worm burden, hepatic granuloma formation, and fibrosis were evaluated. The roles of fasudil on Th17, Treg, and hepatic stellate cells were analyzed. Results: Fasudil therapy markedly reduced the granuloma size and collagen deposit in livers from mice infected with S. japonicum. However, fasudil therapy did not affect the worm burden in infected mice. The underlying cellular and molecular mechanisms were investigated. Fasudil suppressed the activation and induced the apoptosis of CD4+ T cells. Fasudil inhibited the differentiation and effector cytokine secretion of Th17 cells, whereas it upregulated Treg cells in vitro. It also restrained the in vivo interleukin (IL)-4 and IL-17 levels in infected mice. Fasudil directly induced the apoptosis of hepatic stellate cells and downregulated the expressions of hepatic fibrogenic genes, such as collagen type I (Col-I), Col-III, and transforming growth factor-1 (TGF-β1). These effects may contribute to its anti-pathogenic roles in schistosomiasis. Conclusions: Fasudil inhibits hepatic granuloma formation and fibrosis with downregulation of Th17 cells. Fasudil might serve as a novel therapeutic agent for hepatic fibrosis due to schistosome infections and perhaps other disorders.

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“…Finally, the strong anti-fibrotic potential of the pharmacological inhibition of ROCK is in part due to a decrease in the expression of LOX. Indeed, in a model of engineered connective tissue, composed by cardiac fibroblasts and collagen, Rho-associated kinases (ROCK1 and ROCK2) were identified as key mediators of TGF-β-dependent tissue stiffening of engineered heart muscle tissue, and LOX as a downstream target of this ROCK-actin-MRTF/SRF pro-fibrotic signaling pathway [94].…”

Section: Lox/loxls As Pharmacological Targets In Myocardial Diseasesmentioning

confidence: 99%

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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Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Cited by 32 publications

References 79 publications

Sensing and Responding of Cardiomyocytes to Changes of Tissue Stiffness in the Diseased Heart

Sensing and Responding of Cardiomyocytes to Changes of Tissue Stiffness in the Diseased Heart

Inhibition of Rho-Kinase Downregulates Th17 Cells and Ameliorates Hepatic Fibrosis by Schistosoma japonicum Infection

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

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