Trimetazidine effect on phospholipid synthesis in ventricular myocytes: consequences in alpha-adrenergic signaling.
The anti-anginal drug trimetazidine (TMZ) has been shown to increase the synthesis of phospholipids in ventricular myocytes, including phosphatidyl-inositol (PI). This study focused on the consequences of increasing PI metabolism on alpha-adrenergic signaling pathway in cultured rat cardiomyocytes. In the cells treated with TMZ, the synthesis of PI from inositol was largely increased as compared with the control (+55% in 60 min). The stimulation of alpha-adrenergic receptors by phenylephrine (PE) induced a dose-dependent production of inositide phosphates (IPs) by phospholipase C (PLC) activation. However, the amount of available IPs was significantly lower in TMZ-treated cells, in a dose-dependent manner. This effect was observed in the presence and absence of the IP1-phosphatase inhibitor LiCl. The in vitro determination of PLC activity revealed that this effect could not be attributed to the direct inhibition of the enzyme by TMZ. The TMZ-induced reduction of IPs in the PE-stimulated cardiomyocytes should be attributed to the increase of inositol recycling and incorporation in membrane structures, elicited by increased phospholipid synthesis. The consequences of this reduction in IPs availability were investigated on the cardiomyocyte hypertrophy induced by alpha-adrenergic chronic stimulation. Acute stimulation with PE increased protein synthesis (+50%), but this increase was largely prevented by TMZ. In conclusion, TMZ reduces cell available IPs, by accelerating their recycling in membranes as PI. This effect results in a cytoprotection in the pathological process of hypertrophy elicited by chronic alpha-adrenergic stimulation.
Tabbi-Anneni
Iméne
I
INRA-UR1154, Lipides Membranaires et Fonctions Cardiovasculares, Faculté de Pharmacie, Université Paris-sud, Châtenay-Malabry, France.
Lucien
Arnaud
A
Grynberg
Alain
A
D000818:Animals; D051607:CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010656:Phenylephrine; D010716:Phosphatidylinositols / Q000096:biosynthesis; D010743:Phospholipids / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D015398:Signal Transduction; D017855:Transferases (Other Substituted Phosphate Groups) / Q000096:biosynthesis; D014292:Trimetazidine / Q000008:administration & dosage / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000378:metabolism; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D008565:Membrane Proteins; D010716:Phosphatidylinositols; D010743:Phospholipids; D011942:Receptors, Adrenergic, alpha; D014665:Vasodilator Agents; D010656:Phenylephrine; D017855:Transferases (Other Substituted Phosphate Groups); D051607:CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase; C496767:Cdipt protein, rat; D010738:Type C Phospholipases; D014292:Trimetazidine