Endothelin-1 promotes hypertrophic remodelling of cardiac myocytes by activating sustained signalling and transcription downstream of endothelin type A receptors
| Autor: | Emma L. Robinson, Caroline R. Archer, Faye M. Drawnel, H. Llewelyn Roderick |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
RNA
Messenger/genetics 0301 basic medicine MAPK/ERK pathway Male Act D actinomycin D Transcription Genetic β-MHC myosin heavy chain β isoform ANF atrial natriuretic factor Wistar Up-Regulation/drug effects Gene Expression Regulation/drug effects Phenylephrine/pharmacology BNP brain natriuretic factor Transcription Genetic/drug effects Phenylephrine Signal Transduction/drug effects Myocyte Myocytes Cardiac Endothelin A/metabolism Receptor Endothelin-1 Cardiac hypertrophy Signalling MAPK GPCRs DN β-Arr1 dominant negative β-arrestin-1 PE phenylepherine ECE endothelin converting enzyme Receptor Endothelin A Cardiomegaly/genetics Cell biology Up-Regulation NFAT nuclear factor of activated T cells NRVMs neonatal rat ventricular myocytes DPM disintegrations per minute TAC transverse aortic constriction Endothelin receptor ETA receptor endothelin type A receptor Transcription Signal Transduction Agonist ECC excitation contraction coupling Myocytes Cardiac/drug effects medicine.medical_specialty medicine.drug_class Cardiomegaly Biology CVD cardiovascular disease Endocytosis TCA trichloroacetic acid Article CN calcineurin MEF2 myocyte enhancer factor-2 03 medical and health sciences Internal medicine medicine ET-1 endothelin-1 Animals Humans DUSP6 dual specificity phosphatase-6 RNA Messenger Rats Wistar Protein Kinase Inhibitors G protein-coupled receptor IEG immediate early gene Receptor Endothelin A/metabolism Ang II angiotensin II α-MHC myosin heavy chain α isoform Myocytes Genetic/drug effects ETB receptor endothelin type B receptor Cell Biology Newborn Endothelin 1 SRF serum response factor ERK1/2 extracellular signal-regulated kinase 1/2 Rats 030104 developmental biology Endocrinology GPCR G-protein coupled receptor HEK293 Cells Cardiac/drug effects Animals Newborn Gene Expression Regulation Protein Kinase Inhibitors/pharmacology RNA Messenger/genetics Endothelin-1/pharmacology ara-C cytosine b-d-arabinofuranoside PD PD184352 MAPK mitogen activated protein kinase |
| Zdroj: | Cellular Signalling Cellular Signalling, 36, 240-254. Elsevier Science |
| ISSN: | 0898-6568 |
| Popis: | 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 15 min pulse of ET-1 was sufficient to induce markers of hypertrophy that were present when measured at 24 h in vivo and 48 h 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. Highlights • Acute ET-1 exposure elicits a long-lasting cardiac myocyte hypertrophic response. • ET-1 effects depend on persistent MAPK signalling and active transcription. • ET-1 elicited hypertrophy is insensitive to subsequent ETA receptor antagonism. • Endocytosis inhibition potentiates ET-1-induction of hypertrophy markers. • Endocytosis inhibition sensitises effects of ET-1 to ETA receptor antagonist. |
| Databáze: | OpenAIRE |
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