Endothelin-1 promotes hypertrophic remodelling of cardiac myocytes by activating sustained signalling and transcription downstream of endothelin type A receptors

Caroline R Archer, Emma L Robinson, Faye M Drawnel, H Llewelyn Roderick*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


G-protein coupled receptor (GPCR) mediated activation of the MAPK signalling cascade is a key pathway in the induction of hypertrophic remodelling of the heart - a response to pathological cues including hypertension and myocardial infarction. While levels of pro-hypertrophic hormone agonists of GPCRs increase during periods of greater workload to enhance cardiac output, hypertrophy does not necessarily result. Here we investigated the relationship between the duration of exposure to the pro-hypertrophic GPCR agonist endothelin-1 (ET-1) and the induction of hypertrophic remodelling in neonatal rat ventricular myocytes (NRVM) and in the adult rat heart in vivo. Notably, a 15min pulse of ET-1 was sufficient to induce markers of hypertrophy that were present when measured at 24h in vivo and 48h in vitro. The persistence of ET-1 action was insensitive to ET type A receptor (ETA receptor) antagonism with BQ123. The extended effects of ET-1 were dependent upon sustained MAPK signalling and involved persistent transcription. Inhibitors of endocytosis however conferred sensitivity upon the hypertrophic response to BQ123, suggesting that endocytosis of ETA receptors following ligand binding preserves their active state by protection against antagonist. Contrastingly, α1 adrenergic-induced hypertrophic responses required the continued presence of agonist and were sensitive to antagonist. These studies shed new light on strategies to pharmacologically intervene in the action of different pro-hypertrophic mediators.

Original languageEnglish
Pages (from-to)240-254
Number of pages15
JournalCellular Signalling
Publication statusPublished - Aug 2017
Externally publishedYes


  • Animals
  • Animals, Newborn
  • Cardiomegaly/genetics
  • Endothelin-1/pharmacology
  • Gene Expression Regulation/drug effects
  • HEK293 Cells
  • Humans
  • Male
  • Myocytes, Cardiac/drug effects
  • Phenylephrine/pharmacology
  • Protein Kinase Inhibitors/pharmacology
  • RNA, Messenger/genetics
  • Rats, Wistar
  • Receptor, Endothelin A/metabolism
  • Signal Transduction/drug effects
  • Transcription, Genetic/drug effects
  • Up-Regulation/drug effects

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