Endothelin-1 Signaling

Endothelin-1 (ET1) is a vasoconstrictor peptide that is able to induce cardiac hypertrophy. ET1 is the principal isoform in the cardiovascular system and remains the most ubiquitous, potent, and unusually long-lasting constrictor of blood vessels discovered. Biosynthesis of ET1 is primarily regulated by autocrine mechanisms and physico-chemical factors such as mechanical forces, changes in oxygen tension, changes in pH, angiotensin-II, vasopressin, norepinephrine, growth factors, cytokines, lipoproteins and adhesion molecules. Inhibitors of ET1 synthesis include nitric oxide (NO) and its intracellular effectors, cGMP, prostacyclin, atrial natriuretic peptides and steroid hormones. ET1 is also released from endothelial cell-specific storage granules (Weibel-Palade bodies) in response to external physiological, or perhaps pathophysiological stimuli.ET1 has a strong affinity for two receptors (ETA and ETB), which are located on endothelial cells, vascular smooth muscle cells, fibroblasts, and numerous other cell types throughout the body. The two receptors play similar but distinct roles in pathology. Transcription of the endothelin gene results in synthesis of a pre-pro-endothelin-1 peptide, which is cleaved by furin convertases to the inactive precursor peptide of ET1 (big ET1). Big ET1 is then processed by either endothelin converting enzymes (ECE), chymases, MMP2 or secreted soluble endopeptidase. The binding of ET1 to the ETA receptor leads to activation of G-αs and Gαq, and ET binding to the ETB receptor leads to Gαq and Gαi activation. Gαq activates PLC-β, causing release of cytosolic IP3 and membrane-bound DAG. IP3 causes an early rapid release of Ca2+ from intracellular stores. DAG activates PKC, increasing the sensitivity of the contractile apparatus to Ca2+ as well as inducing intracellular signaling mechanisms that promote long-term cellular responses through the MAPK cascade. In addition, ET1 activates PLD and PLA2, the latter increasing the production of arachidonic acid and hence inflammatory mediators produced by COX such as prostaglandins and thromboxanes, and lipooxygenase products such as leukotrienes and lipoxines. Activation of RTK and phosphorylation of PI3K by means of the cytosolic tyrosine kinase c-Src mediate the formation of the SHC-GRB2-SOS complex, leading to Ras activation. As a result, Raf-MAPK pathway is activated, which leads to cell proliferation and migration. Raf also retains an intrinsic anti-apoptotic effect by inhibiting caspase family proteases. Activation of ETB increases cGMP via induction of NO by NOS, which is dependent on calmodulin and the release of Ca2+ from intracellular stores.In the brain, the endothelin system modulates cardiorespiratory centers and release of hormones. In addition to its potent cardiovascular actions, ET1 causes contraction of nonvascular smooth muscle, stimulation of the release of neuropeptides, pituitary hormones, and atrial natriuretic peptide, biosynthesis of aldosterone, modulation of neurotransmitter release, and increase of bone resorption. ET1 also induces the expression of several proto-oncogenes such as c-Fos, c-Jun, and c-Myc. These actions are of potential significance in chronic congestive heart failure, renal disease, hypertension, cerebral vasospasm, and pulmonary hypertension, conditions commonly associated with increased expression of ET1.