In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 96, No. 11 ( 1997-12-02), p. 3954-3962
Abstract:
Background Angiotensin (Ang) II type 1 receptor (AT 1 -R) induces cardiomyocyte hypertrophy and fibroblast proliferation, whereas the physiological role of AT 2 -R in cardiac remodeling remains poorly defined. Methods and Results Using Bio14.6 cardiomyopathic (CM) hamsters, we found that AT 2 -R sites were increased by 153% during heart failure compared with F1B controls. AT 1 -R numbers were increased by 72% in the hypertrophy stage and then decreased to the control level during heart failure. Such differential regulation of AT 2 -R and AT 1 -R during heart failure was consistent with changes in the respective mRNA levels. Autoradiography and immunocytochemistry revealed that both AT 2 -R and AT 1 -R are localized at higher densities in fibroblasts present in fibrous regions. Surrounding myocardium predominantly expressed AT 1 -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 AT 2 -R (30 fmol/mg protein). Using the cardiac fibroblasts expressing AT 2 -R, we found that Ang II stimulated net collagenous protein production by 48% and pretreatment with an AT 2 -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 [ 3 H]thymidine uptake) was significantly increased by PD123319, and the AT 2 -R agonist CGP42112A reduced the serum-stimulated increase in cell numbers by 23%. Treatment with an AT 1 -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 AT 2 -R is reexpressed by cardiac fibroblasts present in fibrous regions in failing CM hearts and that the increased AT 2 -R exerts an anti–AT 1 -R action on the progression of interstitial fibrosis during cardiac remodeling by inhibiting both fibrillar collagen metabolism and growth of cardiac fibroblasts.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/01.CIR.96.11.3954
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
1997
detail.hit.zdb_id:
1466401-X
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