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Cartilage intermediate layer protein 1 (CILP1): A novel mediator of cardiac extracellular matrix remodelling.

ABSTRACT: Heart failure is accompanied by extracellular matrix (ECM) remodelling, often leading to cardiac fibrosis. In the present study we explored the significance of cartilage intermediate layer protein 1 (CILP1) as a novel mediator of cardiac ECM remodelling. Whole genome transcriptional analysis of human cardiac tissue samples revealed a strong association of CILP1 with many structural (e.g. COL1A2 r2?=?0.83) and non-structural (e.g. TGFB3 r2?=?0.75) ECM proteins. Gene enrichment analysis further underscored the involvement of CILP1 in human cardiac ECM remodelling and TGF? signalling. Myocardial CILP1 protein levels were significantly elevated in human infarct tissue and in aortic valve stenosis patients. CILP1 mRNA levels markedly increased in mouse heart after myocardial infarction, transverse aortic constriction, and angiotensin II treatment. Cardiac fibroblasts were found to be the primary source of cardiac CILP1 expression. Recombinant CILP1 inhibited TGF?-induced ?SMA gene and protein expression in cardiac fibroblasts. In addition, CILP1 overexpression in HEK293 cells strongly (5-fold p?

SUBMITTER: van Nieuwenhoven FA

PROVIDER: S-EPMC5700204 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Cartilage intermediate layer protein 1 (CILP1): A novel mediator of cardiac extracellular matrix remodelling.

van Nieuwenhoven Frans A FA Munts Chantal C Op't Veld Roel C RC González Arantxa A Díez Javier J Heymans Stephane S Schroen Blanche B van Bilsen Marc M

Scientific reports 20171122 1

Heart failure is accompanied by extracellular matrix (ECM) remodelling, often leading to cardiac fibrosis. In the present study we explored the significance of cartilage intermediate layer protein 1 (CILP1) as a novel mediator of cardiac ECM remodelling. Whole genome transcriptional analysis of human cardiac tissue samples revealed a strong association of CILP1 with many structural (e.g. COL1A2 r<sup>2</sup> = 0.83) and non-structural (e.g. TGFB3 r<sup>2</sup> = 0.75) ECM proteins. Gene enrichme ...[more]

PMID: 29167509

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Project description:IntroductionThe prevalence of heart failure increases in the aging population and following myocardial infarction (MI), yet the extracellular matrix (ECM) remodeling underpinning the development of aging- and MI-associated cardiac fibrosis remains poorly understood. A link between inflammation and fibrosis in the heart has long been appreciated, but has mechanistically remained undefined. We investigated the expression of a novel protein, extracellular matrix protein 1 (ECM1) in the aging and infarcted heart.MethodsYoung adult (3-month old) and aging (18-month old) C57BL/6 mice were assessed. Young mice were subjected to left anterior descending artery-ligation to induce MI, or transverse aortic constriction (TAC) surgery to induce pressure-overload cardiomyopathy. Left ventricle (LV) tissue was collected early and late post-MI/TAC. Bone marrow cells (BMCs) were isolated from young healthy mice, and subject to flow cytometry. Human cardiac fibroblast (CFb), myocyte, and coronary artery endothelial & smooth muscle cell lines were cultured; human CFbs were treated with recombinant ECM1. Primary mouse CFbs were cultured and treated with recombinant angiotensin-II or TGF-β1. Immunoblotting, qPCR and mRNA fluorescent in-situ hybridization (mRNA-FISH) were conducted on LV tissue and cells.ResultsECM1 expression was upregulated in the aging LV, and in the infarct zone of the LV early post-MI. No significant differences in ECM1 expression were found late post-MI or at any time-point post-TAC. ECM1 was not expressed in any resident cardiac cells, but ECM1 was highly expressed in BMCs, with high ECM1 expression in granulocytes. Flow cytometry of bone marrow revealed ECM1 expression in large granular leucocytes. mRNA-FISH revealed that ECM1 was indeed expressed by inflammatory cells in the infarct zone at day-3 post-MI. ECM1 stimulation of CFbs induced ERK1/2 and AKT activation and collagen-I expression, suggesting a pro-fibrotic role.ConclusionsECM1 expression is increased in ageing and infarcted hearts but is not expressed by resident cardiac cells. Instead it is expressed by bone marrow-derived granulocytes. ECM1 is sufficient to induce cardiac fibroblast stimulation in vitro. Our findings suggest ECM1 is released from infiltrating inflammatory cells, which leads to cardiac fibroblast stimulation and fibrosis in aging and MI. ECM1 may be a novel intermediary between inflammation and fibrosis.

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Cartilage intermediate layer protein 1 (CILP1): A novel mediator of cardiac extracellular matrix remodelling.

Publications

Cartilage intermediate layer protein 1 (CILP1): A novel mediator of cardiac extracellular matrix remodelling.

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