Cardiac Fibrosis in Tg (mREN2)Rats (TGR) Involves Both At-1 and Endothelin Receptors
Ang II plays a role in cardiac hypertrophy (CH) and was associated to cardiac fibrosis (CF). However, data are conflicting on the occurrence of CF and little is known on the mechanisms leading to collagen deposition and CF in TGR, a model of CH with an activated tissue renin-angiotensin system (RAS). Thus, we investigated if: 1) CH is associated with excess collagen deposition; 2) the RAS, and/or the endothelin (ET) system contribute to the development of CF. Four-wk old TGR were body weight (BW)- and blood pressure (BP)-matched randomly allocated to receiving the following (oral) treatments for 4 weeks : placebo (P), Bosentan (100 mg/Kg b.w., B) and Irbesartan (50 mg/kg b.w., I). BW and systolic BP were measured weekly. After rats were euthanized, 5 μm thick equatorial sections of the left ventricle (LV) werestained with Sirius Red to visualize fibrillar collagen. A quantitative analysis of percent collagen areas (CA) was performed with a Leica DM photomicroscope coupled to a PC with Qwin Leica Image Software. Development of severe hypertension and CH was prevented in group I (BP: 160±mmHg; normalized LV wt: 2.28±0.06 mg/g bw, p<0.0001 by ANOVA & Bonferroni test), but not inboth groups P (BP:262±; 3.71±.10) and B (275±; 3.38±.11). At variance, collagen deposition was significantly reduced not only in group I (CA % arb. Units: 1.38±.10) , but also in B (1.33±.10), compared to P (2.19±.40, p<0.0001). Thus, hypertension and CH are associated with excess collagen deposition in the LV of TGR rats. Although both hypertension and CH were prevented by selective AT1 but not mixed ETA/ETB receptor blockade, both treatments hindered CF. Thus, our data show a dissociation between the BP changes and the molecular mechanisms underlying fibrosis, which do and do not involve ET-1, respectively.