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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. METHODS AND 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.

journal_name

Circulation

journal_title

Circulation

authors

Ohkubo N,Matsubara H,Nozawa Y,Mori Y,Murasawa S,Kijima K,Maruyama K,Masaki H,Tsutumi Y,Shibazaki Y,Iwasaka T,Inada M

doi

10.1161/01.cir.96.11.3954

subject

Has Abstract

pub_date

1997-12-02 00:00:00

pages

3954-62

issue

eissn

0009-7322

issn

1524-4539

journal_volume

pub_type

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Angiotensin type 2 receptors are reexpressed by cardiac fibroblasts from failing myopathic hamster hearts and inhibit cell growth and fibrillar collagen metabolism.