Endothelin-3 induces hypertrophy of cardiomyocytes by the endogenous endothelin-1-mediated mechanism.
We have recently reported that endothelin-1 (ET-1) mediates angiotensin II-induced hypertrophy of cardiomyocytes as an autocrine/paracrine factor. In the present study, we examined whether endothelin-3 (ET-3) induces hypertrophy of cultured neonatal rat cardiomyocytes and whether endogenous ET-1 mediates this effect. ET-3 (10(-7) M) increased the cell surface area of cardiomyocytes after 48 h. ET-3 dose dependently (10(-9)-10(-7) M) stimulated protein synthesis as evaluated by [3H]leucine incorporation; the maximum response was 1.4-fold increase over the control at 10(-7) M. Since the response of cardiac hypertrophy is characterized by enhanced expression of fetal isoforms of muscle specific genes, the effect of ET-3 on steady state levels of mRNA for skeletal alpha-actin was evaluated by Northern blot analysis. ET-3 (10(-9)-10(-7) M) increased mRNA level for skeletal alpha-actin with a maximum response after 6 h. ET-3-induced [3H]leucine incorporation, skeletal alpha-actin mRNA and cell surface area were inhibited by a synthetic ETB receptor antagonist (BQ788). Interestingly, ET-3-induced skeletal alpha-actin gene expression and [3H]leucine incorporation were inhibited by a synthetic ETA receptor antagonist (BQ123) as well as by antisense oligonucleotides against peproET-1 mRNA. ET-3 (10(-7) M) transiently increased mRNA levels for ET-1 peaking at 30 min and stimulated the release of immunoreactive ET-1 from cardiomyocytes. These results suggest that endogenous ET-1 locally generated and secreted by cardiomyocytes may contribute to ET-3-induced cardiac hypertrophy as an autocrine/paracrine factor.
Tamamori
M
M
Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
Ito
H
H
Adachi
S
S
Akimoto
H
H
Marumo
F
F
Hiroe
M
M
D000199:Actins / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D001667:Binding, Competitive; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000502:physiology*; D015870:Gene Expression; D006984:Hypertrophy; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000096:biosynthesis; D009206:Myocardium / Q000473:pathology*; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000378:metabolism*
D000199:Actins; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D009124:Muscle Proteins; D016376:Oligonucleotides, Antisense; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D012333:RNA, Messenger; D017466:Receptors, Endothelin; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)