title: Angiotensin type 2 receptors are reexpressed by cardiac fibroblasts from failing myopathic hamster hearts and inhibit cell growth and fibrillar collagen metabolism.
abstract: BACKGROUND
  Angiotensin (Ang) II type 1 receptor (AT1-R) induces cardiomyocyte hypertrophy and fibroblast proliferation, whereas the physiological role of AT2-R in cardiac remodeling remains poorly defined.
  
  
  RESULTS
  Using Bio14.6 cardiomyopathic (CM) hamsters, we found that AT2-R sites were increased by 153% during heart failure compared with F1B controls. AT1-R numbers were increased by 72% in the hypertrophy stage and then decreased to the control level during heart failure. Such differential regulation of AT2-R and AT1-R during heart failure was consistent with changes in the respective mRNA levels. Autoradiography and immunocytochemistry revealed that both AT2-R and AT1-R are localized at higher densities in fibroblasts present in fibrous regions. Surrounding myocardium predominantly expressed AT1-R, but the level of expression was less than that in fibrous regions. Cardiac fibroblasts isolated from CM hearts during heart failure but not from control hamsters expressed AT2-R (30 fmol/mg protein). Using the cardiac fibroblasts expressing AT2-R, we found that Ang II stimulated net collagenous protein production by 48% and pretreatment with an AT2-R antagonist, PD123319, evoked a further elevation (83%). Ang II-induced synthesis of fibronectin and collagen type I were enhanced by 40% and 53%, respectively, by pretreatment with PD123319. Ang II-induced DNA synthesis (assessed by [3H]thymidine uptake) was significantly increased by PD123319, and the AT2-R agonist CGP42112A reduced the serum-stimulated increase in cell numbers by 23%. Treatment with an AT1-R antagonist, TCV116, for 20 weeks inhibited progression of interstitial fibrosis by 28%, whereas with 44-week PD123319 treatment but not 20-week treatment, the extent of the fibrous region was increased significantly, by 29%.
  
  
  CONCLUSIONS
  These findings demonstrate that AT2-R is re-expressed by cardiac fibroblasts present in fibrous regions in failing CM hearts and that the increased AT2-R exerts an anti-AT1-R action on the progression of interstitial fibrosis during cardiac remodeling by inhibiting both fibrillar collagen metabolism and growth of cardiac fibroblasts.
authors.affiliation: Department of Medicine II, Kansai Medical University, Moriguchi, Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Ohkubo
authors.forename: H
authors.initials: H
authors.lastname: Matsubara
authors.forename: Y
authors.initials: Y
authors.lastname: Nozawa
authors.forename: Y
authors.initials: Y
authors.lastname: Mori
authors.forename: S
authors.initials: S
authors.lastname: Murasawa
authors.forename: K
authors.initials: K
authors.lastname: Kijima
authors.forename: K
authors.initials: K
authors.lastname: Maruyama
authors.forename: H
authors.initials: H
authors.lastname: Masaki
authors.forename: Y
authors.initials: Y
authors.lastname: Tsutumi
authors.forename: Y
authors.initials: Y
authors.lastname: Shibazaki
authors.forename: T
authors.initials: T
authors.lastname: Iwasaka
authors.forename: M
authors.initials: M
authors.lastname: Inada
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001345:Autoradiography; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division; D003094:Collagen / Q000378:metabolism*; D006224:Cricetinae; D015342:DNA Probes; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009210:Myofibrils / Q000378:metabolism*; D009929:Organ Size; D011233:Precipitin Tests; D012333:RNA, Messenger / Q000032:analysis; D011945:Receptors, Angiotensin / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D057911:Angiotensin Receptor Antagonists; D015342:DNA Probes; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D003094:Collagen