Dose-dependent activation of distinct hypertrophic pathways by serotonin in cardiac cells.
There is substantial evidence supporting a hypertrophic action of serotonin [5-hydroxytryptamine (5-HT)] in cardiomyocytes. However, little is known about the mechanisms involved. We previously demonstrated that 5-HT-induced hypertrophy depends, in part, on the generation of reactive oxygen species by monoamine oxidase-A (MAO-A) (see Ref. 3). Cardiomyocytes express 5-HT(2) receptors, which may also participate in hypertrophy. Here, we analyzed the respective contribution of 5-HT(2) receptors and MAO-A in H9C2 cardiomyoblast hypertrophy. 5-HT induced a dose-dependent increase in [(3)H]leucine incorporation and stimulation of two markers of cardiac hypertrophy, ANF-luc and alphaSK-actin-luc reporter genes. Experiments using 1 microM 5-HT showed that hypertrophic response occurred independently from MAO-A. Using pharmacological inhibitors (M100907 and ketanserin), we identified a novel mechanism of action involving 5-HT(2A) receptors and requiring Ca(2+)/calcineurin/nuclear factor of activated T-cell activation. The activation of this hypertrophic pathway was fully prevented by 5-HT(2A) inhibitors and was unaffected by MAO inhibition. When 10 microM 5-HT was used, an additional hypertrophic response, prevented by the MAO inhibitors pargyline and RO 41-1049, was observed. Unlike the 5-HT(2A)-receptor-mediated H9C2 cell hypertrophy, MAO-A-dependent hypertrophic response required activation of extracellular-regulated kinases. In conclusion, our results show the existence of a dose-dependent shift of activation of distinct intracellular pathways involved in 5-HT-mediated hypertrophy of cardiac cells.
Villeneuve
C
C
Institut National de la Santé et de la Recherche Médicale, U858, Université de Toulouse, Toulouse, France .
Caudrillier
A
A
Ordener
C
C
Pizzinat
N
N
Parini
A
A
Mialet-Perez
J
J
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D006332:Cardiomegaly / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D007930:Leucine / Q000493:pharmacokinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000633:toxicity*; D018490:Serotonin Agents / Q000633:toxicity*; D014316:Tritium; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology
D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D044402:Receptor, Serotonin, 5-HT2A; D018490:Serotonin Agents; D014316:Tritium; D012701:Serotonin; D008995:Monoamine Oxidase; D019703:Calcineurin; D007930:Leucine