Ang(1-7) influences ET-1 signaling through Mas: ETBR interactions: implications in pulmonary hypertension (original) (raw)

Hood, Katie Y., Yusuf, Hiba, Findlay, Jane E., Santos, Robson A., Castro, Carlos H., Baillie, George S. ORCID: https://orcid.org/0000-0003-2469-6316, MacLean, Margaret R., Montezano, Augusto and Touyz, Rhian M. ORCID: https://orcid.org/0000-0003-0670-0887(2016) Ang(1-7) influences ET-1 signaling through Mas: ETBR interactions: implications in pulmonary hypertension.Journal of Hypertension, 34(Supl 1), e216. (doi: 10.1097/01.hjh.0000500475.07008.db) (PMID:27754060)

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Abstract

Objective: Ang(1-7) has been shown to protect against pulmonary hypertension (PH). Mechanisms remain unclear. Considering the importance of ET-1 in PH pathophysiology and endothelial dysfunction, we questioned whether Ang(1-7) influences ET-1 signaling in endothelial cells and whether Ang(1-7) treatment influences the ET-1 system in PH. Design and Method: Human endothelial cells (hEC) were stimulated with ET-1 in absence/presence of Ang(1-7). Mas and ETBR interaction was observed by immunoprecipitation. To characterize physical interactions, we utilized novel technology, employing a library of peptides spanning the MasR sequence, to define sites of ETBR binding. To investigate pathophysiological significance of our findings, we investigated whether Ang(1-7) treatment ameliorates PH. Hypoxia was used to induce PH in mice: normoxic (NV) and hypoxic vehicle (HV), normoxic (NA) and hypoxic PH (HA) treated with Ang(1-7) 30 [mu]g/kg/day. Results: Ang(1-7) increases ET-1 release (125%) and ETBR protein (50%). ET-1-induced increases in VCAM-1 protein (38%) and TNF[alpha] production (30%) were blocked by Ang(1-7). Pro-inflammatory effects were dependent on NO. Ang(1-7) increased NO production (257%) in a Mas and ETBR-dependent manner. Mutagenesis studies identified regions conferring specificity for ETBR binding. Peptide disruptors to prevent Mas/ETBR interaction were used for in vitro validation. We previously demonstrated in hEC that Ang(1-7) stimulates eNOS phosphorylation (180%), an effect inhibited by pre-incubation with peptide disruptors. In HP mice, RVSP (18.7 NV vs. 47.6mmHg HV, p < 0.05) RVH (0.19 NV vs. 0.28 HV, p < 0.01) and ET-1 levels (0.8 NV vs 2.4pg/ml HV, p < 0.05) were increased and blocked by Ang(1-7). Hypercontractility in pulmonary arteries of HV mice was attenuated by Ang(1-7). Conclusions: These findings indicate that vasoprotective effects of Ang(1-7) may be mediated through Mas:ETBR dimerization. In vivo studies support a relationship between Ang(1-7)/Mas and ET-1 systems. In conclusion we have identified a novel link between Ang(1-7) and ET-1 through physical interactions between Mas and ETBR.

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