Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Jan;168(2):296-317.
doi: 10.1111/j.1476-5381.2012.02195.x.

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

Faye M Drawnel  1 , Caroline R Archer, H Llewelyn Roderick
Affiliations
Review

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

Faye M Drawnel et al. Br J Pharmacol. 2013 Jan.

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 ET(A) 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 articles: This 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-1.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Signalling pathways activated downstream of the ETA receptor in cardiomyocytes. ET-1 binds to the Gαq-coupled ETA receptor inducing production of IP3 and DAG. These second messengers activate protein kinase cascades, ROS production and IP3-induced calcium release. Following ET-1 binding, the ET-1-ETA receptor complex is internalized in a GRK3-β-arrestin dependent manner. β-arrestin has been postulated to induce activation of MAPK cascades.
Figure 2
Figure 2
Excitation–contraction coupling in the cardiomyocyte. Opening of voltage-gated Na+-channels induces cellular depolarization (1). L-type voltage-gated calcium channels are activated in response to depolarization and mediate calcium entry (2). Increased calcium concentration within the cardiac dyad activates the closely opposed RyR2 and induces calcium-induced-calcium release (3), raising cytosolic calcium concentration. Calcium diffuses to the contractile apparatus (4), binds to the contractile filaments and stimulates contraction (5). Calcium is re-sequestered in the sarcoplasmic reticulum or extruded from the cell by NCX, returning cytosolic calcium concentration to resting levels (6). Colocalization of IP3RII within the cardiac dyad facilitates calcium-induced calcium release under stimulated conditions.
Figure 3
Figure 3
ET-1 regulates ventricular myocyte contractility. Downstream of the ETA receptor in the ventricular myocyte, IICR, PKC, PKD, p90 RSK and ERK are activated. Protein-kinase-dependent phosphorylation of NHE1 increases intracellular Na+ concentration and depolarizes the cell. Subsequent activation of NCX in reverse mode allows calcium entry to be enhanced. When combined with PKC-dependent amplification of calcium entry through the L-type calcium channel, the stimulus for CICR is increased. IP3-dependent calcium release from the SR sensitizes the closely opposed RyR2, hence facilitating CICR. The resulting elevated cytosolic calcium concentration and PKC/PKD-dependent phosphorylation of myofilament proteins allows the myocyte to produce a larger force of contraction.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Alexander SPH, Mathie A, Peters JA. Guide to Receptors and Channels (GRAC), 5th edition. Br J Pharmacol. 2011;164:1–2. - PMC - PubMed
    1. Allen BG, Phuong LL, Farhat H, Chevalier D. Both endothelin-A and endothelin-B receptors are present on adult rat cardiac ventricular myocytes. Can J Physiol Pharmacol. 2003;81:95–104. - PubMed
    1. Alvarez BV, Pérez NG, Ennis IL, Camilión de Hurtado MC, Cingolani HE. Mechanisms underlying the increase in force and Ca(2+) transient that follow stretch of cardiac muscle: a possible explanation of the Anrep effect. Circ Res. 1999;85:716–722. - PubMed
    1. Anand I, McMurray J, Cohn JN, Konstam MA, Notter T, Quitzau K, et al. Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:347–354. - PubMed
    1. Anderson ME. Calmodulin kinase signaling in heart: an intriguing candidate target for therapy of myocardial dysfunction and arrhythmias. Pharmacol Ther. 2005;106:39–55. - PubMed

Publication types