Detrimental subtype-specific endothelin-1 (ET-1) signaling in myocardial cells: the ET(A) mediated proliferation and ET(B)receptor down-regulation.
Many physiological and pathological processes in the cardiac tissue have been shown to be associated with a release of endothelin (ET) peptides and with induction of specific ET-receptors and G-protein-coupled ion channels. However, the exact mechanism regulating ET-receptors in the myocardium is controversial. The response to ET-1, the most important member of the ET family, is rapidly attenuated by down-regulation of ET-receptors. The internalization of ET-1 bound to two subclasses of specific receptors (ET(A) and ET(B)) that are abundant in the myocardium has been hypothesized to activate and/or inhibit a variety of intracellular signal transducing systems. The [125I]ET-1, BQ-3020 and selective ET-antagonists were used to study the subtype-selective component of regulation of ET-1 receptors in myocardial membranes. We determined the characteristics of [125I]ET-1 binding and [3H]thymidine incorporation in whole cell saturation studies and measured Ca2+ channel induction and the total number of inactive Ca2+ channels in photoaffinity studies with [3H]azidopine. Here we demonstrate four important components of the complex ET-1 response in human, porcine and rat myocardium, leading to aberrant responses of cells. After ET-1 induction, adaptive subtype-ETB selective down-regulation predominated in human embryonic fibroblasts, in porcine membrane vesicles and in microsomal membranes of renal hypertensive rats, with preferential high affinity ET-1 binding to ETA receptors and with the resultant ETA mediated proliferative and mitogenic activation of human fibroblasts. The ET-1 induction was also accompanied by profound inactivation of Ca2+ channels in myocardial membranes.
Drímal
J
J
Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava, Slovak Republic. exfadrim@savba.sk
Mislovicová
M
M
Ismail
A
A
Moncek
F
F
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D015536:Down-Regulation; D019332:Endothelin-1 / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000378:metabolism; D007457:Iodine Radioisotopes; D008297:Male; D008861:Microsomes / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D015398:Signal Transduction; D013552:Swine
D015220:Calcium Channels; D019332:Endothelin-1; D007457:Iodine Radioisotopes; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D004247:DNA