title: Induction of myocardial biglycan in heart failure in rats--an extracellular matrix component targeted by AT(1) receptor antagonism.
abstract: OBJECTIVE
  Cardiac remodelling associated with congestive heart failure typically involves dilatation of the ventricular cavities, cardiomyocyte hypertrophy and alterations of extracellular matrix. Biglycan is an extracellular proteoglycan with several recently appreciated functions including cell adhesion, collagen fibril assembly, and growth factor interactions. The aims of this study were to investigate the regulation of biglycan expression and to elucidate the site(s) of synthesis of biglycan in myocardial tissue in an experimental model of heart failure (HF).
  
  
  METHODS
  Myocardial tissue samples were obtained from rats with myocardial infarction (MI) subsequent to ligation of the left coronary artery. Northern blot analysis and real-time quantitative RT-PCR were employed to investigate mRNA levels. The cellular distribution of biglycan was analysed by in situ hybridisation and immunohistochemistry.
  
  
  RESULTS
  Myocardial biglycan mRNA levels in non-ischemic tissue of both left and right ventricles of heart failure rats were substantially elevated as compared to sham-operated rats. Although expression levels peaked 7 days after MI (13-fold increase compared to the sham group, P<0.05), substantial elevations of biglycan mRNA were observed throughout the study period. Analysis of cellular distribution revealed that biglycan expression was confined to myocardial fibroblasts and vascular endothelial cells. In cardiac fibroblasts isolated from failing hearts, biglycan mRNA levels were markedly elevated compared with fibroblasts from sham-operated rats. In addition, in rats with ischemic heart failure treatment with the AT(1) receptor antagonist losartan (12.5 mg.kg(-1) b.i.d. per os, for 25 days) prevented the increase of myocardial biglycan as well as TGF-beta(1) mRNA.
  
  
  CONCLUSIONS
  This report demonstrates global induction of myocardial biglycan mRNA in heart failure. Myocardial biglycan expression could be targeted by AT(1) receptor antagonism, an intervention well documented to halt cardiac remodelling in heart failure. Furthermore, the study provides evidence that angiotensin II is a regulator of biglycan expression in cardiac fibroblasts.
authors.affiliation: MSD Cardiovascular Research Centre, Rikshospitalet University Hospital, University of Oslo, Oslo, 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 Øystein
authors.initials: GØ
authors.lastname: Andersen G
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: D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D058578:Biglycan; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D023421:Models, Animal; D009203:Myocardial Infarction / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D058578:Biglycan; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan