Role of myocytes in myocardial collagen production.
Excessive collagen deposition may cause abnormal stiffness of the heart during hypertrophy and heart failure. The potent vasoconstrictor angiotensin II seems, via an unknown mechanism, to stimulate collagen production. This study describes the in vitro and ex vivo effects of [Sar(1)]Ang II on collagen production by fibroblasts in culture and in beating, nonworking heart preparations. The effects of [Sar(1)]Ang II on isolated rat hearts or rat heart fibroblasts were determined by quantifying transcript levels of collagen phenotypes I and III through videodensitometry after Northern blot analysis with specific cDNA probes (collagen [P alpha( 2)r(2)] rat alpha( 2)[I] probe for type I and human skin fibroblast alpha(1)[III] probe for type III). When [Sar(1)]Ang II was added in vitro to neonatal or adult 28-week-old Wistar-Kyoto rat heart fibroblasts, questionable stimulation in the mRNAs of types I and III occurred. In contrast, when 10(-8) mol/L [Sar(1)]Ang II was added to beating, nonworking Wistar-Kyoto rat heart preparation ex vivo, a 1.5- to 2.5-fold stimulation of collagen mRNAs of phenotypes I and III was observed. When neonatal fibroblasts were cocultured with neonatal myocytes in vitro, with 10(-10) mol/L [Sar(1)]Ang II added, there was no stimulation of either phenotype. However, significant stimulation of both collagen transcripts was recorded when 10(-10) mol/L [Sar(1)]Ang II was added to adult fibroblasts cocultured with either neonatal or adult myocytes. Our data suggest that factors produced by myocytes are necessary for upregulation of collagen genes in vitro and demonstrate that fibroblast-myocyte cross-talk is required for Ang II-induced collagen upregulation.
Department of Molecular Cardiology, The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
M
M
Pathak
S
S
Sarkar
E
E
Vellaichamy
S
S
Sen
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D018920:Coculture Techniques; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics; D005347:Fibroblasts; D005355:Fibrosis / Q000517:prevention & control; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D010477:Perfusion; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011921:Rats, Inbred WKY; D015854:Up-Regulation
D012333:RNA, Messenger; D000804:Angiotensin II; D003094:Collagen