title: Connective tissue growth factor--a novel mediator of angiotensin II-stimulated cardiac fibroblast activation in heart failure in rats.
abstract: The pathophysiologic mechanisms of myocardial remodeling in heart failure (HF) remain poorly understood. Using differential mRNA display of myocardial tissue from rats with ischemic HF vs. controls we identified robust myocardial induction of the mRNA encoding connective tissue growth factor (CTGF). The aim of this study was to investigate the sites of synthesis and the mechanisms of induction of CTGF in failing myocardial tissue. The study demonstrates that myocardial expression of CTGF mRNA and protein is substantially elevated in non-ischemic tissue from both the left and the right ventricles of rats with experimentally induced myocardial infarction (MI). The induction of myocardial CTGF mRNA was shown to transcend from early post-infarction HF to chronic HF. In situ hybridization and immunohistochemical analysis of myocardial tissue sections demonstrated expression of CTGF confined to fibroblasts and endothelial cells of non-ischemic myocardial tissue. In subsequent experiments rats subjected to MI were randomized to treatment with the AT1 angiotensin receptor antagonist losartan (12.5 mg/kg b.i.d. per os) or vehicle. Losartan attenuated ventricular hypertrophy, improved hemodynamics, and prevented the induction of myocardial CTGF mRNA observed in rats post-MI. To provide the cellular basis of Ang II-stimulated CTGF mRNA expression, primary cultures of rat myocardial fibroblasts were stimulated with Ang II (10(-7) M). Real-time reverse transcription-polymerase chain reaction and western blot analysis demonstrate that Ang II induces rapid, AT1 receptor-mediated elevations of CTGF mRNA and protein in rat cardiac fibroblasts. Furthermore, CTGF was shown to stimulate fibroblast proliferation in vitro. In conclusion, this study demonstrates that CTGF is a myocardial effector of Ang II-induced myocardial remodeling in HF mediated via AT1 receptors situated on cardiac fibroblasts.
authors.affiliation: MSD Cardiovascular Research Center, Rikshospitalet University Hospital, University of Oslo, Oslo N-0027, Norway.
authors.forename: Mohammed Shakil
authors.initials: MS
authors.lastname: Ahmed
authors.forename: Erik
authors.initials: E
authors.lastname: Øie
authors.forename: Leif Erik
authors.initials: LE
authors.lastname: Vinge
authors.forename: Arne
authors.initials: A
authors.lastname: Yndestad
authors.forename: Geir
authors.initials: G
authors.lastname: Øystein Andersen
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Andersson
authors.forename: Toril
authors.initials: T
authors.lastname: Attramadal
authors.forename: Håvard
authors.initials: H
authors.lastname: Attramadal
mesh_terms: D000284:Administration, Oral; D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage*; D002303:Cardiac Output, Low / Q000378:metabolism; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D019808:Losartan / Q000008:administration & dosage*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000889:Anti-Arrhythmia Agents; C526316:CCN2 protein, rat; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D019808:Losartan