Abstract DAROC-2
ENDOTHELIN-1 AS A TARGET FOR INTERVENTION IN METABOLIC SYNDROME LOW-TONE HO Departments of Medical Research and Internal Medicine, Taipei Veterans General Hospital, and National YangMing University School of Medicine
“Metabolic Syndrome” (Mets) is a cluster of “pre-disease states” including diabetes, hypertension, dyslipidemia and obesity, with common roots in insulin resistance (IR) and low grade systemic inflammation (LGSI). The molecular mechanism linking high blood pressure (BP) and glucose (PG) in Mets is still not clear. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictive polypeptide with action much longer than another similarly potent angiotensin-II (AT2). Both ET-1 and AT2 are well known deeply involved in pathophysiology of hypertension and many other cardiovascular events. We firstly discovered ET-1 inhibited insulin-stimulated-glucose-uptake (ISGU) in rat adipocyte via ET-1 receptor and post-insulin binding mechanism. A series of subsequent experiments have accumulated convincing evidences supporting its pivotal role in the development of Mets in rats. These include as following: (1) Modest hyperinsulinemia (HI) induced by exogenous insulin caused sequential elevations in order of plasma triglyceride (TG) and ET-1 levels, then BP and PG finally, of which BP elevation was abolished by pretreatment with ET-1 receptor A antagonist (ETARA). (2) Similarly an endogenous HI model of fructose fed rat (FFR) also showed same phenomena. (3) Increase of plasma ET-1 level and sensitivity to ET-1 induced aortic ring constriction was found in the FFR and also upregulation of mRNA of ET-1 and ETAR in their tail vessel walls. (4) Infusion of physiological doses of ET-1 in conscious rats induced IR shown by glucose clamp and mild PG elevation. (5) AT2 enhanced ET-I induced vasoconstriction via upregulating ETAR in aortic ring, and via increase of binding capacity and decrease of binding affinity to ETAR in the aortic tissue of a high fat rat (HFR) model of Mets. (6) Combination of sub-pressor doses of ET-1 and AT2 caused persistent hypertension. (7) Other evidence related to ET-1’s role in atherosclerosis: enhance lipolysis in vivo and in vitro; decrease of cholesterol efflux from macrophages via degradation of ABCG1; and stimulation of proliferation and migration of vascular smooth muscle cells (VSMC), etc. In summary of these evidences, a hypothesis may be formed so that ET-1 may negatively interact with insulin in its metabolic pathway, i.e., IR, in conjunction with its vasoconstrictive potency to induce hypertension, and meanwhile synergistically with its mitogenic pathway, e.g., proliferation and migration of VSMC, fatty acid metabolism interact with inflammatory macrophage and foam cells to induce atherosclerosis. Suffice it to say, ET-1 serves well as a target for intervention of Mets in animal models. Although there are a few ET-1 receptor antagonists are available in clinical use, better efficacy and safety profiles are yet to find, in aspects of either intervention or prevention of Mets in clinical trials. A platform of high throughput cell based drug screening system has been established, which composed of ETAR and ETBR transfected cell lines for both screening and counter-screening purposes. However, it always needs luck in the realm of drug discovery. 43
