Mechanisms of endothelin-1 induced reactive oxygen species production in vascular adventitial fibroblasts

With the relationship between endothelin-1 (ET-1) stimulation and reactive oxygen species (ROS) production unknown in adventitial fibroblasts, I examined the ROS response to ET-1 and angiotensin (Ang II).;ET-1-induced ROS peaked following 4 hrs of ET-1 stimulation and was inhibited by an ETA receptor antagonist (BQ 123, 1 muM) an extracellular signal-regulated kinase (ERK) 1/2 inhibitor (PD98059, 10 muM), and by both a specific, apocynin (10 muM), and non-specific, diphenyleneiodonium (10 muM), NAD(P)H oxidase inhibitor. NOX2 knockout fibroblasts did not produce an ET-1 induced change in ROS levels.;Ang II treatment increased ROS levels in a biphasic manner, with the second peak occurring 6 hrs following stimulation. The secondary phase of Ang II induced ROS was inhibited by an AT1 receptor antagonist, Losartan (100 muM) and BQ 123.;In conclusion, ET-1 induces ROS production primarily through an ET A-ERK1/2 NOX2 pathway, additionally, Ang II-induced ROS production also involves an ETA pathway.