title: CTGF knockout does not affect cardiac hypertrophy and fibrosis formation upon chronic pressure overload.
abstract: BACKGROUND
  One of the main contributors to maladaptive cardiac remodeling is fibrosis. Connective tissue growth factor (CTGF), a matricellular protein that is secreted into the cardiac extracellular matrix by both cardiomyocytes and fibroblasts, is often associated with development of fibrosis. However, recent studies have questioned the role of CTGF as a pro-fibrotic factor. Therefore, we aimed to investigate the effect of CTGF on cardiac fibrosis, and on functional, structural, and electrophysiological parameters in a mouse model of CTGF knockout (KO) and chronic pressure overload.
  
  
  RESULTS
  A new mouse model of global conditional CTGF KO induced by tamoxifen-driven deletion of CTGF, was subjected to 16weeks of chronic pressure overload via transverse aortic constriction (TAC, control was sham surgery). CTGF KO TAC mice presented with hypertrophic hearts, and echocardiography revealed a decrease in contractility on a similar level as control TAC mice. Ex vivo epicardial mapping showed a low incidence of pacing-induced ventricular arrhythmias (2/12 in control TAC vs. 0/10 in CTGF KO TAC, n.s.) and a tendency towards recovery of the longitudinal conduction velocity of CTGF KO TAC hearts. Picrosirius Red staining on these hearts unveiled increased fibrosis at a similar level as control TAC hearts. Furthermore, genes related to fibrogenesis were also similarly upregulated in both TAC groups. Histological analysis revealed an increase in fibronectin and vimentin protein expression, a significant reduction in connexin43 (Cx43) protein expression, and no difference in NaV1.5 expression of CTGF KO ventricles as compared with sham treated animals.
  
  
  CONCLUSIONS
  Conditional CTGF inhibition failed to prevent TAC-induced cardiac fibrosis and hypertrophy. Additionally, no large differences were found in other parameters between CTGF KO and control TAC mice. With no profound effect of CTGF on fibrosis formation, other factors or pathways are likely responsible for fibrosis development.
authors.affiliation: Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Magda S C
authors.initials: MS
authors.lastname: Fontes
authors.affiliation: Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Elise L
authors.initials: EL
authors.lastname: Kessler
authors.affiliation: Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Leonie
authors.initials: L
authors.lastname: van Stuijvenberg
authors.affiliation: Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Maike A
authors.initials: MA
authors.lastname: Brans
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Lucas L
authors.initials: LL
authors.lastname: Falke
authors.affiliation: Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: Kok
authors.affiliation: Department of Dentistry, University of Western Ontario, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Leask
authors.affiliation: Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Harold V M
authors.initials: HV
authors.lastname: van Rijen
authors.affiliation: Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Goldschmeding
authors.affiliation: Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: A.A.B.vanVeen@umcutrecht.nl.
authors.forename: Toon A B
authors.initials: TA
authors.lastname: van Veen
mesh_terms: D000818:Animals; D001011:Aorta / Q000601:surgery; D001391:Azo Compounds; D053840:Brugada Syndrome / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000075224:Cardiac Conduction System Disease; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055513:Connective Tissue Growth Factor / Q000172:deficiency / Q000235:genetics*; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D003251:Constriction, Pathologic / Q000150:complications / Q000601:surgery; D004452:Echocardiography; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D011312:Pressure; D015398:Signal Transduction; D020257:Ventricular Remodeling; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: D001391:Azo Compounds; C526318:CCN2 protein, mouse; D018031:Connexin 43; D005353:Fibronectins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; D014746:Vimentin; C009798:C.I. direct red 80; D055513:Connective Tissue Growth Factor
keywords: Arrhythmias; CTGF; Fibrosis; Hypertrophy