The role of the paracrine/autocrine mediator endothelin‐1 in regulation of cardiac contractility and growth

Abstract

Endothelin-1 (ET-1) is a critical autocrine and paracrine regulator of cardiac physiology and pathology. Produced locally within the myocardium in response to diverse mechanical and neurohormonal stimuli, ET-1 acutely modulates cardiac contractility. During pathological cardiovascular conditions such as ischaemia, left ventricular hypertrophy and heart failure, myocyte expression and activity of the entire ET-1 system is enhanced, allowing the peptide to both initiate and maintain maladaptive cellular responses. Both the acute and chronic effects of ET-1 are dependent on the activation of intracellular signalling pathways, regulated by the inositol-trisphosphate and diacylglycerol produced upon activation of the ETA receptor. Subsequent stimulation of protein kinases C and D, calmodulin-dependent kinase II, calcineurin and MAPKs modifies the systolic calcium transient, myofibril function and the activity of transcription factors that coordinate cellular remodelling. The precise nature of the cellular response to ET-1 is governed by the timing, localization and context of such signals, allowing the peptide to regulate both cardiomyocyte physiology and instigate disease. LINKED ARTICLESThis article is part of a themed section on Endothelin. To view the other articles in this section visit http://dx.doi.org/ 10.1111/bph.2013.168.issue-2 AbbreviationsAngII, angiotensin II; CICR, calcium-induced-calcium release; Cn, calcineurin; ECC, excitation-contraction-coupling; IICR, IP3-induced calcium release; IP3R, inositol triphosphate receptor; MyBP-C, myosin binding protein C; RyR, ryanodine receptor; TnI, troponin I IntroductionEndothelin (ET)-1, ET-2 and ET-3 are a family of cyclic 21 amino acid peptides. The peptides are encoded within three separate yet highly conserved genes located on chromosomes 6, 1 and 20 in humans respectively (Inoue et al., 1989). ET-1 is the most well characterized member of this family. The peptide was initially isolated from the culture supernatant of porcine aortic endothelial cells and identified as a proteasesensitive vasoconstrictor. It remains the most potent vasoactive substance identified to date (Yanagisawa et al., 1988), performing an important function in the regulation of vascular smooth muscle tone. ET-1 also mediates effects on other cell types. Here, we discuss the role of ET-1 in the heart. We will focus on the actions of ET-1 on cardiac muscle and describe how the ET system contributes to cardiac regulation and autoregulation during health and disease. ET-1 in the heartThroughout life, ET-1 plays key roles in many aspects of cardiac physiology and pathology. It is involved in controlling aortic arch formation during development (Kurihara et al., 1995), is required for cardiomyocyte survival and prevents myocyte loss during ageing (Zhao et al., 2006). In the adult, ET-1 modulates coronary blood flow by regulation of vascular tone. Furthermore, by acting on its receptors expressed by atrial and ventricular myocytes, the peptide modulates cardiac muscle function directly (Hirata ...

A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes

“…Ang II, insulin, lipopolysaccharide (LPS), and hydrogen peroxide (H 2 O 2 ) were used to mimic these settings as described elsewhere [10, 22–24]. The effects of pro-hypertrophic factors, ET-1 [25] and TGFβ1 [26] on release of exosomes from neonatal CFs were also studied. We measured the total amount of proteins (concentrations), the activity of acetylcholinesterase (AChE), an exosome specific enzyme [27] and protein expression levels of TSG101 and CD63, two exosome markers [5, 6] in total exosomes released from the same number of CFs after the treatment as mentioned above.…”

RhoA signaling in cardiomyocytes protects against stress-induced heart failure but facilitates cardiac fibrosis

“…We found that SERCA mRNA abundance was decreased to a greater extent in hearts from RhoA fl/fl -Cre mice than in those from control mice (Figure 2C), suggesting a greater decrease in cardiac function and contractility (30). Next, we measured effects on calcium transient in individual cardiomyocytes left unstimulated or stimulated with endothelin-1 (ET-1), a neurohumoral agonist that mimics chronic stress in the heart (31). Basal and stimulated calcium transients were significantly lower in RhoA fl/fl -Cre cardiomyocytes than in control cells (Figure 2C), suggesting that RhoA might be involved in mediating increased calcium cycling in response to cardiac stress.…”

Functionally redundant control of cardiac hypertrophic signaling by inositol 1,4,5-trisphosphate receptors

“…Previously, the IP 3 R-2 was thought to be the predominant isoform expressed in the heart. Consequently, most of the studies that focus on the role of IP 3 R in the heart have focused solely on IP 3 R-2 function [13, 33]. However, global genetic knockout of the IP 3 R-2 in mice does not cause any significant difference in the hypertrophic response in pressure overload or dilated cardiomyopathy mouse models [17].…”