Endothelin-1 and smooth muscle cells - Induction of Jun amino-terminal kinase through an oxygen radical-sensitive mechanism

Endothelin-1 (ET-1) has been proposed to contribute to atherogenesis and pl aque rupture in coronary heart disease through activation of mitogen-activa ted protein kinases (MAPKs) in smooth muscle cells (SMCs), Reactive oxygen species (ROS) have been shown to be important signal transduction molecules in SMCs, Thus, the present study aimed to assess the role of ROS in ET-1-m ediated activation of c-Jun amino-terminal kinase (JNK) and extracellular s ignal-regulated kinase (ERK) 1/2, Rat SMCs were exposed to ET-1 over time a t concentrations from 10(-6) to 10(-10) mol/L, and MAPK activity was quanti fied. Activation of JNK and ERK was observed with a maximum stimulation at 10(-7) mol/L ET-1, JNK and ERK were activated by ET-I binding to a single r eceptor (ET-1A) but differed in their downstream mechanisms: only JNK activ ation was sensitive to the radical scavenger N-acetylcysteine and diphenyle ne iodonium, an inhibitor of NADPH oxidase, indicating a role for ROS, The downstream MAPK effector and proinflammatory transcription factor, the acti vator protein-1 complex, was maximally activated 2 hours after the addition of ET-I. It was mainly composed of the JNK substrate c-Jun, and activation was also dependent on ROS formation. We suggest that plaque activation by ET-1 can be mediated through ROS. It can be hypothesized that the clinical benefit of antioxidants in the treatment of atherogenesis may partially dep end on neutralization of ET-1-mediated ROS production.