The Role of Calcium-Sensing Receptors in Endothelin-1-Dependent Effects on Adult Rat Ventricular Cardiomyocytes: Possible Contribution to Adaptive Myocardial Hypertrophy.
Nitric oxide (NO)-deficiency as it occurs during endothelial dysfunction activates the endothelin-1 (ET-1) system and increases the expression of receptor activity modifying protein (RAMP)-1 that acts as a chaperon for calcium-sensing receptors (CaR) that have recently been identified to improve cardiac function. Here, we hypothesized that ET-1 increases the cardiac expression of CaR and thereby induces an adaptive type of hypertrophy. Expressions of RAMP-1, endothelin receptors, and CaR were analyzed by RT-PCR in left ventricular tissues of L-NAME-treated rats. Effects of ET-1 on CaR expression and cell function (load free cell shortening) were analyzed in adult rat ventricular cardiomyocytes. siRNA directed against CaR and RAMP-1 was used to investigate a causal relationship. PD142893 and BQ788 were used to dissect the contribution of ETB1, ETB2, and ETAreceptors. Non-specific NO synthase inhibition with L-Nitro arginine methyl ester (L-NAME) caused a cardiac upregulation of ETBreceptors and CaR suggesting a paracrine effect of ET-1 on cardiomyocytes. Indeed, ET-1 induced the expression of CaR in cultured cardiomyocytes. Under these conditions, cardiomyocytes increased cell size (hypertrophy) but maintained normal function. Inhibition of ETAand ETB1receptors led to ET-1-dependent reduction in cell shortening and attenuated up-regulation of CaR. Down-regulation of RAMP-1 reduced CaR responsiveness. In conclusion, ET-1 causes an adaptive type of hypertrophy by up-regulation of CaR in cardiomyocytes via ETAand/or ETB1receptors. J. Cell. Physiol. 232: 2508-2518, 2017. © 2016 Wiley Periodicals, Inc.
Physiologisches Institut, Justus-Liebig-Universität Gießen, Giessen, Germany.|Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.
Elena
E
Dyukova
Physiologisches Institut, Justus-Liebig-Universität Gießen, Giessen, Germany.
Rolf
R
Schreckenberg
Physiologisches Institut, Justus-Liebig-Universität Gießen, Giessen, Germany.
Christoph
C
Arens
Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.
Guzel
G
Sitdikova
Physiologisches Institut, Justus-Liebig-Universität Gießen, Giessen, Germany.
Klaus-Dieter
KD
Schlüter
D000222:Adaptation, Physiological; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000067268:Isolated Heart Preparation; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D019899:Paracrine Communication; D034622:RNA Interference; D017208:Rats, Wistar; D058262:Receptor Activity-Modifying Protein 1 / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
D019332:Endothelin-1; C545508:Ramp1 protein, rat; D058262:Receptor Activity-Modifying Protein 1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D044169:Receptors, Calcium-Sensing; C473605:extracellular calcium cation-sensing receptor, rat; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase