title: Endothelin-1 is involved in mechanical stress-induced cardiomyocyte hypertrophy.
abstract: We have recently shown that mechanical stress induces cardiomyocyte hypertrophy partly through the enhanced secretion of angiotensin II (ATII). Endothelin-1 (ET-1) has been reported to be a potent growth factor for a variety of cells, including cardiomyocytes. In this study, we examined the role of ET-1 in mechanical stress-induced cardiac hypertrophy by using cultured cardiomyocytes of neonatal rats. ET-1 (10(-8) approximately 10(-7) M) maximally induced the activation of both Raf-1 kinase and mitogen-activated protein (MAP) kinases at 4 and 8 min, respectively, followed by an increase in protein synthesis at 24 h. All of these hypertrophic responses were completely blocked by pretreatment with BQ123, an antagonist selective for the ET-1 type A receptor subtype, but not by BQ788, an ET-1 type B receptor-specific antagonist. BQ123 also suppressed stretch-induced activation of MAP kinases and an increase in phenylalanine uptake by approximately 60 and 50%, respectively, but BQ788 did not. ET-1 was constitutively secreted from cultured cardiomyocytes, and a significant increase in ET-1 concentration was observed in the culture medium of cardiomyocytes after stretching for 10 min. After 24 h, an approximately 3-fold increase in ET-1 concentration was observed in the conditioned medium of stretched cardiomyocytes compared with that of unstretched cardiomyocytes. ET-1 mRNA levels were also increased at 30 min after stretching. Moreover, ET-1 and ATII synergistically activated Raf-1 kinase and MAP kinases in cultured cardiomyocytes. In conclusion, mechanical stretching stimulates secretion and production of ET-1 in cultured cardiomyocytes, and vasoconstrictive peptides such as ATII and ET-1 may play an important role in mechanical stress-induced cardiac hypertrophy.
authors.affiliation: Third Department of Internal Medicine, University of Tokyo School of Medicine and the Health Service Center, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamazaki
authors.forename: I
authors.initials: I
authors.lastname: Komuro
authors.forename: S
authors.initials: S
authors.lastname: Kudoh
authors.forename: Y
authors.initials: Y
authors.lastname: Zou
authors.forename: I
authors.initials: I
authors.lastname: Shiojima
authors.forename: Y
authors.initials: Y
authors.lastname: Hiroi
authors.forename: T
authors.initials: T
authors.lastname: Mizuno
authors.forename: K
authors.initials: K
authors.lastname: Maemura
authors.forename: H
authors.initials: H
authors.lastname: Kurihara
authors.forename: R
authors.initials: R
authors.lastname: Aikawa
authors.forename: H
authors.initials: H
authors.lastname: Takano
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D006332:Cardiomegaly / Q000503:physiopathology*; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000096:biosynthesis / Q000494:pharmacology* / Q000502:physiology*; D004789:Enzyme Activation; D006321:Heart / Q000187:drug effects; D007700:Kinetics; D020929:Mitogen-Activated Protein Kinase Kinases; D004676:Myelin Basic Protein / Q000378:metabolism; D009200:Myocardial Contraction; D009500:Neutralization Tests; D010456:Peptides, Cyclic / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology*; D013314:Stress, Mechanical; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D000906:Antibodies; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D004676:Myelin Basic Protein; D010456:Peptides, Cyclic; D011518:Proto-Oncogene Proteins; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013777:Tetrazoles; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C072247:cyclo(Trp-Asp-Pro-Val-Leu); C081643:candesartan