Abstract 374: Involvement Of RhoA/Rho Kinase Signaling In Dehydroepiandrosterone’s Protective Effect Against Pulmonary Hypertension
RhoA/Rho kinase (ROCK) signaling appears to play a key role in the pathogenesis of experimental pulmonary hypertension (PH). We have previously reported that dehydroepiandrosterone (DHEA) prevents and reverses monocrotaline (MCT)-induced severe occlusive PH in pneumonectomized rats, but the responsible mechanisms are unclear. The aim of this study was to investigate if RhoA/ROCK signaling was involved in DHEA’s protective effect. We studied 4 groups of left lung pneumonectomized rats. Two wks after the surgery, 2 groups received MCT (60 mg/kg, sc) and the other 2 received saline (CON), and thereafter one of each group was fed with 1% DHEA containing rat food for 3 wks. DHEA almost completely inhibited the MCT-induced increase in pulmonary artery (PA) pressure, right ventricular hypertrophy, and PA remodeling. MCT increased RhoA activity and induced caspase-3 activation and ROCK I cleavage (130 kDa, constitutive activation), which were associated with an increase in ROCK activity (as reflected by an increased phosphorylation of MYPT1) in lungs. These MCT-induced changes in protein expression were nearly normalized by DHEA (figure⇓). We also assessed the survival of MCT-injected pneumonectomized rats, and found that DHEA, started 3 wks after MCT injection, resulted in a 100% survival rate in contrast to 30% in DHEA-untreated rats. These results suggest that inhibition of RhoA/ROCK signaling is an important component of DHEA’s impressive protection against MCT-induced severe PH in pneumonectomized rats.