Is the cytoprotective effect of trimetazidine associated with lipid metabolism?
Trimetazidine is an anti-ischemic compound devoid of hemodynamic effect, which was recently suspected to induce cardioprotection at the cellular level by a mechanism involving lipid metabolism. The effect on trimetazidine was evaluated in vivo by determination of rat cardiac fatty acid composition, and in vitro by investigation of the phospholipid metabolism in cultured rat cardiomyocytes. In rats, a 4-week trimetazidine treatment induced a significant decrease in the phospholipid content in linoleic acid, balanced by a small increase in oleic and stearic acids. These changes were not correlated with similar alterations in plasma fatty acid composition. In isolated cells, the time-dependent incorporation of labeled precursors of membrane phospholipid ([3H]inositol, [14C]ethanolamine, [14C]choline, [3H]glycerol, [14C]arachidonic acid, and [14C]linoleic acid 10 micromol/L) was compared in trimetazidine-treated cells and control cells. In trimetazidine-treated cells, arachidonic acid incorporation was increased in the phospholipid, but not in other lipid fractions. This enhanced fatty acid utilization elicited a net increase in the total arachidonic acid uptake. The incorporation of [14C] inositol in phosphatidylinositol was strongly stimulated by trimetazidine, although the uptake of inositol was not altered. The difference was significant within 30 minutes, and reached +70%(in trimetazidine-treated cells) after 150 minutes. A similar result was obtained with ethanolamine as phosphatidylethanolamine precursor, where turnover increased by 50% in trimetazidine-treated cells. Conversely, the incorporation of choline in phosphatidylcholine was not significantly affected by the presence of trimetazidine. In conclusion, trimetazidine appears to interfere with the metabolism of phospholipids in cardiac myocytes in a manner that could indicate an increased phosphatidylinositol turnover and a redirection of cytidine triphosphate (CTP) utilization toward phosphatidylethanolamine instead of phosphatidylcholine turnover. This overall phospholipid turnover increase may contribute to a reorganization of the fatty acid utilization balance in the heart, which could lead to a lowered availability of fatty acids for energy production.
Sentex
E
E
I.N.R.A., Unité de Nutrition Lipidique, Dijon, France.
Sergiel
J P
JP
Lucien
A
A
Grynberg
A
A
D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects; D002794:Choline / Q000378:metabolism; D002849:Chromatography, Gas; D019856:Ethanolamine / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D007294:Inositol / Q000378:metabolism; D019787:Linoleic Acid / Q000378:metabolism; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019301:Oleic Acid / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D010743:Phospholipids / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D013229:Stearic Acids / Q000378:metabolism; D014292:Trimetazidine / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D005227:Fatty Acids; D010714:Phosphatidylethanolamines; D010716:Phosphatidylinositols; D010743:Phospholipids; D013229:Stearic Acids; D014665:Vasodilator Agents; D019301:Oleic Acid; C031183:stearic acid; D007294:Inositol; D019856:Ethanolamine; D019787:Linoleic Acid; D002794:Choline; D014292:Trimetazidine