Chronic
pulmonary hypertension (PH) leads to right-ventricular failure (RVF) characterized by RV remodeling.
Ventricular remodeling is emerging as an important process during
heart failure and recovery. Remodeling in RVF induced by PH is not fully understood. Recently we discovered that
estrogen (E2)
therapy can rescue severe preexisting PH. Here, we focused on whether E2 (42.5 μg·kg(-1)·day(-1), 10 days) can reverse adverse RV structural and extracellular matrix (ECM) remodeling induced by PH using
monocrotaline (MCT, 60 mg/kg). RV
fibrosis was evident in RVF males. Intact females developed less severe RV remodeling compared with males and ovariectomized (OVX) females. Novel ECM-degrading
disintegrin-
metalloproteinases ADAM15 and ADAM17 transcripts were elevated ∼2-fold in all RVF animals. E2
therapy reversed RV remodeling in all groups. In vitro, E2 directly inhibited ANG II-induced expression of
fibrosis markers as well as the
metalloproteinases in cultured cardiac fibroblasts.
Estrogen receptor-β agonist
diarylpropionitrile (
DPN) but not
estrogen receptor-α agonist 4,4',4″-(4-propyl-[1H]-
pyrazole-1,3,5-triyl)trisphenol (PPT) was as effective as E2 in inhibiting expression of these genes. Expression of ECM-interacting cardiac fetal-gene
osteopontin (OPN) also increased ∼9-fold in RVF males. Intact females were partially protected from OPN upregulation (∼2-fold) but OVX females were not. E2 reversed OPN upregulation in all groups. Upregulation of OPN was also reversed in vitro by E2. Plasma OPN was elevated in RVF (∼1.5-fold) and decreased to control levels in the E2 group. RVF resulted in elevated Akt phosphorylation, but not ERK, in the RV, and E2
therapy restored Akt phosphorylation. In conclusion, E2
therapy reverses adverse RV remodeling associated with PH by reversing
fibrosis and upregulation of novel ECM
enzymes ADAM15, ADAM17, and OPN. These effects are likely mediated through
estrogen receptor-β.