Endothelin-1 Signaling Pathway
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Endothelin-1 Signaling Pathway
Cardiac hypertrophy describes an abnormal condition where the heart becomes enlarged. Several factors, such as increased mechanical loading and neuro-hormonal chemicals can induce hypertrophy. ET1 (Endothelin-1) is a 21-amino acid vasoconstrictor peptide, which is able to induce cardiac hypertrophy. In mammals this peptide family also includes ET2 and ET3. ET1 is the principal isoform in the human cardiovascular system and remains the most ubiquitous, potent, and unusually long-lasting constrictor of human vessels discovered. Biosynthesis of ET1 is primarily regulated by autocrine mechanisms, physico-chemical factors, including 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 NO (Nitric Oxide) and its intracellular effectors, cGMP (cyclic Guanosine Monophosphate), prostacyclin, atrial natriuretic peptides and steroid hormones (Ref.1). The peptide is also released from endothelial cell-specific storage granules (Weibel-Palade bodies) in response to external physiological, or perhaps pathophysiological, stimuli producing further vasoconstriction. ET2 is present in human cardiovascular tissues and is potent a vasoconstrictor as ET1 in human arteries and veins. Endothelial cells do not synthesize ET3, but the mature peptide is detectable in plasma and other tissues, including heart and brain (Ref.2).

ET 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 (Ref.3). Transcription of preproendothelin gene expression results in synthesis of the 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 ECEs (Endothelin Converting Enzymes), Chymase, vascular smooth muscle chymase, MMP2 (Matrix Metalloproteinase-2) or secreted soluble endopeptidase (Ref.1). The binding of ET to the ETA receptor leads to activation of the G-proteins; GN-AlphaS and G-AlphaQ, and ET binding to the ETB receptor leads to G-AlphaQ and GN-AlphaI activation. G-AlphaQ activates PLC-Beta (Phospholipase-C-Beta) causing release of cytosolic IP3 (Inositol 1,4,5-trisphosphate) and membrane-bound DAG (Diacylglycerol). IP3 causes an early rapid increase in Ca2+ through its release from intracellular stores. DAG activates PKC (Protein Kinase-C), increasing the sensitivity of the contractile apparatus to Ca2+ as well as inducing intracellular signaling mechanisms that promote long-term cellular responses (proliferation and migration) through the MAPK (Mitogen Activated Protein Kinase) cascade. In addition, ET activates PLD (Phospholipase-D) and PLA2 (Phospholipase-A2), the latter increasing the production of Arachidonic Acid and hence COX (Cyclooxygenase) products (Ptg (Prostaglandins) and Thromboxanes) and lipooxygenase products (Leukotrienes and Lipoxines) (Ref.4). Transactivation of RTK (Receptor Tyrosine Kinase) and phosphorylation of PI3K (Phosphatidylinositol 3-Kinase) by means of the cytosolic tyrosine kinase c-Src mediate the formation of the SHC-GRB2 (Growth Factor Receptor-Bound Protein-2) and 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 (Nitric Oxide Synthase), which is dependent on the release of Ca2+ from intracellular stores and Calm (Calmodulin). ET1 also stimulates COX activity, resulting primarily in increases in PtgI2 (Prostaglandin-I2) with small increases in cAMP or Thromboxane A2, which occurs via ETA induction of PLA2 and COX2 (Ref.5).

ETs can be considered stress-responsive regulators working in paracrine and autocrine fashion in a variety of organs, with both beneficial and detrimental roles in mammals. In the vessels, the endothelin system has a basal vasoconstricting role and participates in development of atherosclerosis and subarachnoid hemorrhage. In the heart, it affects inotropy and chronotropy, and it mediates cardiac remodeling in congestive heart failure. Dysfunction of the ET system may contribute to the etiology and progression of PAH (Pulmonary Arterial Hypertension), a progressive and fatal condition of the cardiopulmonary system (Ref.6). In the lungs, the endothelin system regulates the tone of pulmonary airways and vessels and is involved in development of pulmonary hypertension. In the kidney, it controls water and sodium excretion and acid-base balance, and it participates in the pathophysiology of acute and chronic renal failure. In the brain, the endothelin system modulates cardiorespiratory centers and release of hormones. In addition to the organs described in this review, ET affects the physiology and pathophysiology of the liver, muscle, bones, skin, prostrate, adipose tissue, and reproductive tract (Ref.3). In addition to its potent cardiovascular actions, ET1 causes contraction of nonvascular smooth muscle (intestinal, tracheal, bronchial, mesangial, bladder, uterine, and prostatic 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. Furthermore, ET1 has mitogenic properties, causing proliferation and hypertrophy of vascular smooth muscle, cardiac myocytes, mesangium, bronchial smooth muscle, and fibroblasts. ET1 also induces the expression of several proto-oncogenes (c-Fos, c-Jun, c-Myc, etc). 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 (Ref.4).