Collective transcriptomic deregulation of hypertrophic and dilated cardiomyopathy – Importance of fibrotic mechanism in heart failure

Malgija, Beutline; Kumar, Nachimuthu Senthil; Shanmughavel, P.

doi:10.1016/j.compbiolchem.2018.01.011

Cited by 10 publications

(12 citation statements)

References 65 publications

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“…Our finding of increased FMOD levels in experimental and clinical HF is in line with recent bioinformatics data on differentially expressed genes in myocardial tissue from patients with hypertrophic and dilated cardiomyopathy [ 25 ]. The up-regulation of FMOD was stronger (6-10-fold in AB mice) than that of other SLRPs with a known role in the heart, i.e.…”

Section: Discussionsupporting

confidence: 89%

“…In skin scars, FMOD regulates fibrotic responses through interaction with transforming growth factor (TGF)β [ 20 , 21 ]. Although FMOD is expressed in the heart [ 22 – 25 ], its role remains largely unknown. Here, we investigated the role of FMOD in cardiac remodeling responses in myocardial biopsies from HF patients, in vivo by subjecting FMOD knock-out (FMOD-KO) mice to aortic banding (AB), and in vitro by adenoviral overexpression of FMOD in CM and cardiac fibroblast (CFB) primary cultures.…”

Section: Introductionmentioning

confidence: 99%

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The extracellular matrix proteoglycan fibromodulin is upregulated in clinical and experimental heart failure and affects cardiac remodeling

Andenæs¹,

Lunde²,

Mohammadzadeh³

et al. 2018

PLoS ONE

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Pressure overload of the heart leads to cardiac remodeling that may progress into heart failure, a common, morbid and mortal condition. Increased mechanistic insight into remodeling is instrumental for development of novel heart failure treatment. Cardiac remodeling comprises cardiomyocyte hypertrophic growth, extracellular matrix alterations including fibrosis, and inflammation. Fibromodulin is a small leucine-rich proteoglycan that regulates collagen fibrillogenesis. Fibromodulin is expressed in the cardiac extracellular matrix, however its role in the heart remains largely unknown. We investigated fibromodulin levels in myocardial biopsies from heart failure patients and mice, subjected fibromodulin knock-out (FMOD-KO) mice to pressure overload by aortic banding, and overexpressed fibromodulin in cultured cardiomyocytes and cardiac fibroblasts using adenovirus. Fibromodulin was 3-10-fold upregulated in hearts of heart failure patients and mice. Both cardiomyocytes and cardiac fibroblasts expressed fibromodulin, and its expression was increased by pro-inflammatory stimuli. Without stress, FMOD-KO mice showed no cardiac phenotype. Upon aortic banding, left ventricles of FMOD-KO mice developed mildly exacerbated hypertrophic remodeling compared to wild-type mice, with increased cardiomyocyte size and altered infiltration of leukocytes. There were no differences in mortality, left ventricle dilatation, dysfunction or expression of heart failure markers. Although collagen amount and cross-linking were comparable in FMOD-KO and wild-type, overexpression of fibromodulin in cardiac fibroblasts in vitro decreased their migratory capacity and expression of fibrosis-associated molecules, i.e. the collagen-cross linking enzyme lysyl oxidase, transglutaminase 2 and periostin. In conclusion, despite a robust fibromodulin upregulation in clinical and experimental heart failure, FMOD-KO mice showed a relatively mild hypertrophic phenotype. In cultured cardiac fibroblasts, fibromodulin has anti-fibrotic effects.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

The extracellular matrix proteoglycan fibromodulin is upregulated in clinical and experimental heart failure and affects cardiac remodeling

Andenæs¹,

Lunde²,

Mohammadzadeh³

et al. 2018

PLoS ONE

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“…Additionally, TGF-beta signaling pathway, which is relatively negative enriched in TUBA3D, participates in pathogenesis and development of HCM. Malgija et al indicated that Smad-dependent TGFβ1 pathway was depicted as collagen-gene promoter thus causing cardiac brosis (33). Hedgehog signaling pathway, which possesses numerous roles since embryonic stage and keeps active in the adult, has been enriched in all real hub genes except COL16A1.…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Modules and Hub Genes in Hypertrophic Cardiomyopathy Based on Integrative Weighted Gene Co-expression Network Analysis

Jiang

Chen

Xie

et al. 2021

Preprint

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BackgroundHypertrophic cardiomyopathy (HCM) is a heterogeneously inherited cardiac disorder with unclear biological pathogenesis. This study aims to identify the key modules and genes involved in the development of HCM.MethodsUsing weighted gene co-expression network analysis (WGCNA) algorithm, we constructed integrative co-expression networks for the two large sample HCM datasets separately. After selecting clinically significant modules with the same clinical trait, functional enrichment analysis was performed to detect their common pathways. Based on the intramodular connectivity (IC), the shared hub genes were generated, validated, and further explored in gene set enrichment analysis (GSEA).ResultsThe orange and pink modules in GSE141910, the green and brown modules in GSE36961 were mostly related to HCM. Functional enrichment analysis suggested that HCM might exhibit enhanced processes including remodeling of extracellular matrix, activation of abnormal protein signaling, aggregation of calcium ion, and organization of cytoskeleton. SMOC2, COL16A1, RASL11B, TUBA3D, IL18R1 were defined as real hub genes due to their top IC values, significantly different expression levels, and excellent diagnostic performance in both datasets. Moreover, GSEA analysis demonstrated that pathways of the five hub genes were mainly involved in neuroactive ligand-receptor interaction, ECM-receptor interaction, Hedgehog signaling pathway.ConclusionOur study provides more comprehensive insights into the molecular mechanisms of HCM, identifies five hub genes as candidate biomarkers for HCM, which might be theoretically feasible for targeted therapy against HCM.

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“…In the cardiovascular system, lumican is independently associated with carotid atherosclerotic plaques in patients with essential hypertension 14 . Transcriptome analysis of hypertrophic and dilated cardiomyopathy revealed that SLRPs (keratocan, fibromodulin), ECM‐related proteins, and the complement system are involved in the regulation of fibrosis mechanisms in heart failure 15 . The study also found that decorin, biglycan, podocan, and TSK were significantly elevated in diet‐induced obese mice and db/db diabetes model mice, indicating that they may be a secreted protein associated with obesity and type 2 diabetes 10,16–18 .…”

Section: Introductionmentioning

confidence: 99%

Novel roles of Tsukushi in signaling pathways and multiple disease processes

Deng

Guo

et al. 2021

BioFactors

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Tsukushi (TSK), a newly identified hepatokine, is a member of the small leucine‐rich proteoglycans (SLRPs) family. TSK was originally isolated and identified in the lens of the chicken. Preliminary research on TSK has focused on its role in various physiological processes such as growth and development, wound healing, and cartilage formation. In recent years, the role of TSK in regulating cell signaling pathways, cell proliferation, and differentiation has been studied. In addition, the research has gradually expanded to the fields of glycolipid metabolism and energy balance. This article briefly reviews the role of TSK in the physiological and pathological process.

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Collective transcriptomic deregulation of hypertrophic and dilated cardiomyopathy – Importance of fibrotic mechanism in heart failure

Cited by 10 publications

References 65 publications

The extracellular matrix proteoglycan fibromodulin is upregulated in clinical and experimental heart failure and affects cardiac remodeling

The extracellular matrix proteoglycan fibromodulin is upregulated in clinical and experimental heart failure and affects cardiac remodeling

Identification of Key Modules and Hub Genes in Hypertrophic Cardiomyopathy Based on Integrative Weighted Gene Co-expression Network Analysis

Novel roles of Tsukushi in signaling pathways and multiple disease processes

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