Cardiomyocytes facing fibrotic conditions re-express extracellular matrix transcripts

Heras-Bautista, Carlos O; Mikhael, Nelly; Lam, Jessica; Shinde, Vaibhav; Katsen-Globa, Alisa; Dieluweit, Sabine; Molcanyi, Marek; Uvarov, V.; Jütten, Peter; Sahito, Raja Ghazanfar Ali; Mederos-Henry, Francisco; Piechot, Alexander; Brockmeier, Konrad; Hescheler, Jürgen; Sachinidis, Agapios; Pfannkuche, Kurt

doi:10.1016/j.actbio.2019.03.017

Cited by 54 publications

(42 citation statements)

References 44 publications

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“…Fibroblasts are an abundant and reactive cell type in the heart, readily transforming into myofibroblasts and increasing their secretion of ECM and cytokines in response to a large number of endocrine, paracrine, and mechanical signals that include transforming growth factor β (TGFβ), ROS, angiotensin, aldosterone, ECM changes, and many others [115,116]. Cardiomyocytes help drive the fibrotic process by dying and leaving a vacancy that must be filled in with ECM, and also by secreting their own signaling molecules and collagen to contribute to the process [117]. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) modulate the turnover of the deposited ECM through their respective actions of promoting and inhibiting the degradation of matrix components like collagen.…”

Section: Pathophysiological Mechanisms Of Dystrophic Cardiomyopathymentioning

confidence: 99%

Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy

Meyers

Townsend

2019

IJMS

114

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Duchenne muscular dystrophy (DMD) is a devastating disease featuring skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. Historically, respiratory failure has been the leading cause of mortality in DMD, but recent improvements in symptomatic respiratory management have extended the life expectancy of DMD patients. With increased longevity, the clinical relevance of heart disease in DMD is growing, as virtually all DMD patients over 18 year of age display signs of cardiomyopathy. This review will focus on the pathophysiological basis of DMD in the heart and discuss the therapeutic approaches currently in use and those in development to treat dystrophic cardiomyopathy. The first section will describe the aspects of the DMD that result in the loss of cardiac tissue and accumulation of fibrosis. The second section will discuss cardiac small molecule therapies currently used to treat heart disease in DMD, with a focus on the evidence supporting the use of each drug in dystrophic patients. The final section will outline the strengths and limitations of approaches directed at correcting the genetic defect through dystrophin gene replacement, modification, or repair. There are several new and promising therapeutic approaches that may protect the dystrophic heart, but their limitations suggest that future management of dystrophic cardiomyopathy may benefit from combining gene-targeted therapies with small molecule therapies. Understanding the mechanistic basis of dystrophic heart disease and the effects of current and emerging therapies will be critical for their success in the treatment of patients with DMD.

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Section: Pathophysiological Mechanisms Of Dystrophic Cardiomyopathymentioning

confidence: 99%

Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy

Meyers

Townsend

2019

IJMS

114

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“…Our EL proteomic data identified the presence of multiple protein hits relevant to diseases that have been linked to dysfunctional lysosomal enzymes. These include lysosomal α-glucosidase (GAA), a key lysosomal enzyme involved in the degradation of glycogen in lysosomes 72 , the lysosomal protective protein/cathepsin A/H0VMB1, which serves a protective function by regulating stability and activity of beta-galactosidase and neuraminidase enzymes 73 and also plays a role in galactosialidosis 74 , Clusterin/H0VVP2, identified as a potential biomarker for the lysosomal storage disorder mucopolysaccharidosis 75 , and Decorin, a protein that when dysregulated contributes to cardiac fibrosis or fibrotic stiffness 76 . Glycogen phosphorylase, brain form (PYGB), is a lysosomal enzyme identified in our EL fraction that regulates glycogen mobilization 77 , and plays a prominent role as the only marker protein elevated in the early-stage of asymptomatic patients with Fabry disease 78 .…”

Section: Discussionmentioning

confidence: 99%

Cardiac Atrial Compartmentalisation Proteomics: A Modified Density Gradient Method to Analyse Endo-lysosomal Proteins

Ayagama

Bose

Capel

et al. 2021

Preprint

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The importance of lysosomes in cardiac physiology and pathology are well established, and evidence for roles in calcium signalling are emerging. We describe a label-free proteomics method suitable for small cardiac tissue biopsies based on density-separated fractionation, which allows study of endo-lysosomal (EL) proteins. Density gradient fractions corresponding to tissue lysate; sarcoplasmic reticulum (SR), mitochondria (Mito) (1.3 g/ml); and EL with negligible contamination from SR or Mito (1.04 g/ml), were analysed using Western Blot, enzyme activity assay and LC-MS/MS analysis (adapted discontinuous Percoll, and sucrose differential density gradient). Kyoto Encyclopedia of Genes and Genomes, Reactome, Panther and Gene Ontology pathway analysis showed good coverage of RAB proteins and lysosomal cathepsins (including cardiac-specific cathepsin D) in the purified EL fraction. Significant EL proteins recovered included catalytic activity proteins. We thus present a comprehensive protocol and dataset of guinea-pig atrial EL organelle proteomics using techniques also applicable for non-cardiac tissue.

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“…Soft matrix conditions also resulted in comparative transcriptomes in contrast to cardiomyocytes exposed to a stiff hydrogel. Gene expression analyses of cardiomyocytes grown on stiff matrices revealed many deregulated genes, especially of genes related to developmental programs (Heras-Bautista et al, 2019). In addition, cardiomyocytes grown under stiff matrix conditions also upregulated different ECM-components or modulators, such as the collagens Col1a1, Col1a2, Col4a2, Col6a3, and Col8a2, matrix metalloproteinases, inhibitors of matrix metalloproteinases, and tenascinC, (Heras-Bautista et al, 2019).…”

Section: Consequences Of Stiffness Changes On Cardiomyocyte Performancementioning

confidence: 99%

“…Gene expression analyses of cardiomyocytes grown on stiff matrices revealed many deregulated genes, especially of genes related to developmental programs (Heras-Bautista et al, 2019). In addition, cardiomyocytes grown under stiff matrix conditions also upregulated different ECM-components or modulators, such as the collagens Col1a1, Col1a2, Col4a2, Col6a3, and Col8a2, matrix metalloproteinases, inhibitors of matrix metalloproteinases, and tenascinC, (Heras-Bautista et al, 2019). Similarly, bovine and murine adult cardiac side population progenitor cells were cultured on substrates with a stiffness corresponding with that of physiological or fibrotic myocardium.…”

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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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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Cardiomyocytes facing fibrotic conditions re-express extracellular matrix transcripts

Cited by 54 publications

References 44 publications

Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy

Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy

Cardiac Atrial Compartmentalisation Proteomics: A Modified Density Gradient Method to Analyse Endo-lysosomal Proteins

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

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