Endothelin is a 21 amino acid peptide synthesized as three isopeptides by vascular endothelial cells exposed to various types of stress or injury. All major organs including lung, kidney heart, brain and liver have been shown to both produce and respond to the agonist effects of endothelin in autocrine and paracrine signaling mechanisms. The liver is one of the most responsive tissues exhibiting both hemodynamic and glycogenolytic responses at low nM concentrations and specific signal transduction responses in cultured hepatic-derived cells at pM concentrations. The objective of the proposed research program is to characterize regulatory mechanisms in which endothelin participates in the mammalian liver in physiological and pathophysiological situations. Specific experimental goals include: a) characterization of endothelin-mediated signaling mechanisms or responses in hepatic-derived cultured cells; specifically, endothelin receptors on sinusoidal endothelial cells will be identified and characterized and endothelin-mediated synthesis of lipid and peptide secondary messengers will be characterized; b) investigation of the capability of hepatic sinusoidal endothelial cells to synthesize endothelin and the elucidation of factors and conditions which regulate endothelin synthesis; c) characterization of endothelin-mediated signaling mechanism operative in various pathophysiological models of systemic and hepatic injury such as endotoxic shock, hepatic ischemia/reperfusion injury, and obstructive jaundice. Successful outcomes from the proposed research will provide mechanistic insight into the role and the importance of probably the most potent vasoactive mediator yet discovered in the hepatic responses to inflammation/injury. Understanding the biochemical or molecular details of the endothelin receptor-mediated signaling mechanisms and the metabolic functions which are responsive to endothelin in pathophysiological episodes may facilitate the development of appropriate therapeutic interventions designed to minimize or ameliorate impairment of hepatic function following exposure to systemic or specific hepatic trauma.
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