H2S and no generate nitroxyl and activate hno-trpa1-cgrp pathway for neurovascular control.
MIRJAM EBERHARDT; MARIA DUX; BARBARA NAMER; JAN MILJKOVIC; NADA CORDASIC; CHRISTINE WILL; TATJANA I. KICHKO; JEANNE DE LA ROCHE; MICHAEL FISCHER; DAMIAN BIKIEL; SEBASTIAN SUAREZ; KAROLA DORSCH; ANDREAS LEFFLER; ALEXANDRU BABES; ANGELIKA LAMPERT; JOCHEN K. LENNERZ; JOHANNES JACOBI; MARCELO MARTI; FABIO DOCTOROVICH; EDWARD D. HÖGESTÄTT; PETER M. ZYGMUNT; IVANA IVANOVIC-BURMAZOVIC; KARL MESSLINGER; PETER REEH; MILOS R FILIPOVIC
The Macmillan Campus
Nitroxyl (HNO) is a redox sibling of nitric oxide (NO) that targets distinct signaling pathways with pharmacological endpoints of high significance in the treatment of heart failure. Beneficial HNO effects depend, in part, on its ability to release calcitonin gene-related peptide (CGRP) through an unidentified mechanism. We now provide evidence that HNO is generated in reaction of two gasotransmitters, NO and H2S, leading to activation of TRPA1 via formation of N-terminal disulfide bonds, which results in prolonged channel activation. As a consequence of the subsequent Ca2+ influx, CGRP is released that induces local and systemic vasodilation. H2S production co-localizes with TRPA1. H2S-evoked vasodilatatory effects largely depend on its reaction with NO to form HNO and activate the TRPA1-CGRP pathway. The body-wide representation of the neuroendocrine HNO-TRPA1-CGRP pathway constitutes an essential control element of the cardiovascular system.