Cardiac fibrosis occurs early and involves endothelin and AT-1 receptors in hypertension due to endogenous angiotensin II

Objectives We investigated if endothelin (ET)-1 and the renin-angiotensin-aldosterone system play a role in cardiac fibrosis. Background Angiotensin II (Ang II) can induce cardiac fibrosis, but the underlying mechanisms are incompletely understood. Methods Four-week-old transgenic (mRen2)27 rat (TGRen2) received for four weeks a placebo, the mixed ETA/ETB endothelin receptor antagonist bosentan, the angiotensin II type I receptor (AT-1) antagonist irbesartan, the ETA endothelin receptor antagonist BMS-182874, and a combined treatment with irbesartan plus BMS-182874. We measured collagen density on Sirius red–stained serial sections of the left ventricle (LV) with a photomicroscope equipped with specific software and assessed the gene expression of procollagen α1(I), atrial natriuretic peptide (ANP), transforming growth factor-beta 1 (TGFβ1), endothelin converting enzyme, and ETB receptor. Results In the placebo group, hypertension was associated with LV hypertrophy and cardiac fibrosis (LV weight: 4.0 ± 0.3 mg/g body weight; collagen density: 2.21 ± 0.16%), which were all prevented with irbesartan (2.3 ± 0.1, 1.30 ± 0.13, p < 0.001), but not with BMS-182874 (4.0 ± 0.2, 2.41 ± 0.22). Bosentan also prevented fibrosis (1.39 ± 0.18) but not hypertension and LV hypertrophy (3.38 ± 0.27). Combined irbesartan and BMS-182874 treatment prevented LV hypertrophy (2.9 ± 0.1) but not fibrosis (2.52 ± 0.16). Collagen density correlated (r = 0.414, p < 0.05) with plasma aldosterone levels. In TGRen2 with LV hypertrophy, the gene expression of ANP and ETB but not that of TGFβ1 and procollagen α1(I) was increased. Conclusions In Ang II–dependent hypertension, cardiac fibrosis was associated with LV hypertrophy and was hindered by both mixed ETA/ETB blockade and AT-1 blockade. Only the latter treatment prevented both hypertension and LV hypertrophy. Thus, there is a dissociation between the mechanisms of cardiac fibrosis and hypertension, which do and do not entail ET-1, respectively.