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.