title: Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease.
abstract: OBJECTIVE
  We sought to determine whether the cardiac renin-angiotensin system (RAS) is activated in human aortic valve disease depending on left ventricular function, and we analyzed the concomitant regulation of the extracellular matrix components.
  
  
  BACKGROUND
  In animal models with pressure or volume load, activation of the cardiac RAS increases fibrosis. In human aortic valve disease, the ventricular collagen protein content is increased, but only scarce data on the activation state of the cardiac RAS and its effects on collagen and fibronectin messenger ribonucleic acid (mRNA) are available.
  
  
  METHODS
  In left ventricular biopsies from patients with aortic valve stenosis (AS) and aortic valve regurgitation and from control subjects, we quantitated mRNAs for angiotensin-converting enzyme (ACE), chymase, transforming growth factor-beta1 (TGF-beta1), collagen I, collagen III and fibronectin by reverse-transcription polymerase chain reaction. Proteins were localized by immunohistochemistry; ACE activity was determined by high performance liquid chromatography; and TGF-beta protein by quantitative enzyme immunoassay.
  
  
  RESULTS
  Protein, ACE and TGF-beta1 mRNA were significantly increased in patients with AS and AR (1.5- to 2.1-fold) and correlated with each other. The increase occurred also in patients with normal systolic function. Collagen I and III and fibronectin mRNAs were both upregulated about twofold in patients with AS and AR. In AS, collagen and fibronectin mRNA expression levels were positively correlated with left ventricular end-diastolic pressure and inversely with left ventricular ejection fraction (LVEF).
  
  
  CONCLUSIONS
  In human hearts, pressure and volume overload increases cardiac ACE and TGF-beta1 in the early stages. This activation of the cardiac RAS may contribute to the observed increase in collagen I and III and fibronectin mRNA expression. The increase in extracellular matrix already exists in patients with a normal LVEF, and it increases with functional impairment.
authors: Innere Medizin, Kardiologie, Charite, Humboldt Universität Berlin und Deutsches Herzzentrum, Germany.
authors: J
authors: J
authors: Fielitz
authors: S
authors: S
authors: Hein
authors: V
authors: V
authors: Mitrovic
authors: R
authors: R
authors: Pregla
authors: H R
authors: HR
authors: Zurbrügg
authors: C
authors: C
authors: Warnecke
authors: J
authors: J
authors: Schaper
authors: E
authors: E
authors: Fleck
authors: V
authors: V
authors: Regitz-Zagrosek
mesh_terms: D000368:Aged; D001022:Aortic Valve Insufficiency / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000473:pathology*; D003094:Collagen / Q000235:genetics*; D005260:Female; D005353:Fibronectins / Q000235:genetics*; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013318:Stroke Volume / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D005353:Fibronectins; D012333:RNA, Messenger; D003094:Collagen