title: β-Arrestins regulate human cardiac fibroblast transformation and collagen synthesis in adverse ventricular remodeling.
abstract: Cardiac fibroblasts (CFs) produce and degrade the myocardial extracellular matrix and are critical in maladaptive ventricular remodeling that can result in heart failure (HF). β-Arrestins are important signaling molecules involved in β-adrenergic receptor (β-AR) desensitization and can also mediate signaling in a G protein-independent fashion. We hypothesize that β-arrestins play an important role in the regulation of adult human CF biology with regard to myofibroblast transformation, increased collagen synthesis, and myocardial fibrosis which are important in the development of HF. β-Arrestin1 & 2 expression is significantly upregulated in adult human CF isolated from failing left ventricles and β-AR signaling is uncoupled with loss of β-agonist-mediated inhibition of collagen synthesis versus normal control CF. Knockdown of either β-arrestin1 or 2 restored β-AR signaling and β-agonist mediated inhibition of collagen synthesis. Overexpression of β-arrestins in normal CF led to a failing phenotype with increased baseline collagen synthesis, impaired β-AR signaling, and loss of β-agonist-mediated inhibition of collagen synthesis. β-Arrestin knockdown in failing CF diminished TGF-β stimulated collagen synthesis and also inhibited ERK phosphorylation. Overexpression of β-arrestins in normal CF increased basal ERK1/2 and Smad2/3 phosphorylation and enhanced TGF-β-stimulated collagen synthesis. This was prevented by pre-treatment with a MEK1/2 inhibitor. Enhanced β-arrestin signaling appears to be deleterious in CF by promoting a pro-fibrotic phenotype via uncoupling of β-AR signaling as well as potentiating ERK and Smad signaling. Targeted inhibition of β-arrestins in CF may represent a therapeutic strategy to prevent maladaptive myocardial fibrosis.
authors.affiliation: Department of Surgery, Section of Cardiac and Thoracic Surgery, The University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: Jinju
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Surgery, Section of Cardiac and Thoracic Surgery, The University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Philip
authors.affiliation: Department of Surgery, Division of Cardiothoracic Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Xianyao
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Surgery, Section of Cardiac and Thoracic Surgery, The University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: Tiju
authors.initials: T
authors.lastname: Theccanat
authors.affiliation: Department of Surgery, Division of Cardiothoracic Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Abdur Razzaque
authors.affiliation: Department of Surgery, Division of Cardiothoracic Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. Electronic address: akhter@surgery.wisc.edu.
authors.forename: Shahab A
authors.initials: SA
authors.lastname: Akhter
mesh_terms: D019390:Arrestins / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D024022:Fibrillar Collagens / Q000096:biosynthesis*; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D009206:Myocardium / Q000473:pathology*; D058628:Myofibroblasts / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology; D020257:Ventricular Remodeling; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D024022:Fibrillar Collagens; D011943:Receptors, Adrenergic, beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D000071557:beta-Arrestins; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Heart failure; Receptors; Signal transduction