title: S100A1 from Damaged Cardiomyocytes Elicits a Chemoattractant Cardiac Fibroblast Phenotype
creator: Didrihsone, Ieva
subject: ddc-570
subject: 570 Life sciences
description: Despite advancement of therapeutic strategies, myocardial infarction (MI) and subsequent heart failure are still the leading causes of death and disability worldwide. Development of new therapeutic approaches is hampered by insufficient knowledge of the cellular and molecular mechanisms underlying myocardial repair. S100A1 is a Ca2+ governing protein in cardiomyocytes. When released upon MI, S100A1 targets neighboring cardiac fibroblasts and is thereby essential for preserving the left ventricular function. The aim of this study was to systematically assess the phenotype of cardiac fibroblasts in response to extracellular S100A1 by comprehensive gene expression and protein profile analysis.  In order to mimic the ischemic myocardium, adult rat cardiac fibroblasts were exposed to extracellular S100A1. Using RNA microarray technology, a time-resolved transcriptome analysis revealed a rapid activation of gene sets involved in chemoattractance alongside downregulation of pro-fibrotic genes. Since the dominant functional changes comprised secreted proteins, a complete secretome analysis of the cardiac fibroblast supernatant was performed by mass spectrometry. On protein level, enrichment analysis highlighted chemotaxis, chemokine receptor binding, and chemokine activity as the predominantly increased categories upon exposure to S100A1. Chemoattractants formed the most abundantly secreted group of proteins in S100A1-treated cardiac fibroblasts, with CCL2 showing the highest quantity. A prominent early-onset increase of CCL2 expression and secretion in response to S100A1 was confirmed by qPCR and ELISA. S100A1-induced CCL2 expression increase was abolished by chemical inhibition and siRNA knockdown of TLR4.   This study demonstrates for the first time a rapid transformation of cardiac fibroblasts into a chemoattractant phenotype upon exposure to S100A1 from damaged cardiomyocytes. These results suggest a novel role for cardiac fibroblasts as the initial link between ischemic injury and the influx of inflammatory cells in the process of myocardial repair.
date: 2017
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/22835/1/Dissertation%20Ieva%20Didrihsone%20PDF%20A.pdf
identifier: DOI:10.11588/heidok.00022835
identifier: urn:nbn:de:bsz:16-heidok-228353
identifier:   Didrihsone, Ieva  (2017) S100A1 from Damaged Cardiomyocytes Elicits a Chemoattractant Cardiac Fibroblast Phenotype.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/22835/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng