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 (10maximally 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 receptorspecific 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 ϳ3-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.Cardiac hypertrophy, a major underlying cause of heart diseases such as myocardial infarction and cardiac arrhythmias (1), is formed when increased external stimuli such as hemodynamic overload and neurohumoral factors are continuously imposed on cardiac myocytes (2, 3). These external stimuli are generally transduced into the nucleus through protein kinase cascades of phosphorylation (4), and Raf-1 kinase (Raf-1) 1 (5) and mitogen-activated protein (MAP) kinases (6, 7) are important components in these cascades. We have recently reported that stretching of cardiomyocytes sequentially activates Raf-1 and MAP kinases, followed by an increase in protein synthesis (8). Interestingly, all of these events were partially suppressed by a specific antagonist of the angiotensin II (ATII) type 1 receptor, CV11974 (9). These results suggest that mechanical stress exemplified by stretching might stimulate the secretion of ATII from cardiomyocytes and that ATII participates in the activation of the protein kinase cascades and the production of cardiomyocyte hypertrophy through the ATII type 1 receptor. However, because the inhibition of these hypertrophic events by CV11974 is incomplete, factors other than ATII should also be involved in cardiomyocyte hypertrophy induced by mechanical stress.Endothelin-1 (ET-1) ...

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

“…Nuclear localization of ECE-1a and ECE-1b has already been demonstrated in human microvascular endothelial cells, human umbilical vein endothelial cells, and transfected CHO cells [69,70]. Moreover, ET-1 is produced, stored and secreted by neonatal [71] and adult cardiac ventricular myocytes [72] under basal conditions, and regulated in response to stretch [73], electrical stimulation [72], or extracellular ET-1 (Supplemental Figure 2). Interestingly, although the basal level of ET-1 production in ventricular myocytes from failing hearts is unchanged, the effect of electrical stimulation on ET-1 secretion is reduced [72].…”

Role of tissue angiotensin II in myocardial remodelling induced by mechanical stress

“…On the contrary, we have recently elucidated the association of endothelin-1 (ET-1) with mechanical stretch-induced hypertrophic responses. 22 BQ123, an antagonist selective for the ETA receptor subtype, diminished stretch-induced activation of MAP kinase and an increase in phenylalanine uptake by approximately 60% and 50%, respectively, but an ETB receptor-specific antagonist, BQ788, did not. ET-1 was constitutively secreted from cardiomyocytes, and a significant increase in ET-1 concentration was observed in the culture medium of cardiomyocytes in response to stretch for 10 min.…”

Cirrhotic cardiomyopathy

“…The resultant higher cellular sodium content in fibroblasts can significantly increase their mitogenic potential, leading to increased fibrosis [61]. Alternatively, it has been suggested that high sodium intake stimulates the intracardiac production of various cytokines, including transforming growth factor (TGF)-b. TGF-b in turn, acts in an autocrine or paracrine fashion to increase the production of endothelin 1 [62], which also has direct trophic effects on the myocardium [63]. Human studies have also reported a correlation between the sodium intake and left ventricular wall thickness [64].…”