Cardiac mitochondrial alterations induced by insulin deficiency and hyperinsulinaemia in rats: Targeting membrane homeostasis with trimetazidine

Abstract

The present study investigated the ability of trimetazidine (TMZ) to maintain cardiac mitochondrial function during the development of insulin deficiency and hyperinsulinaemia. The anti-ischaemic drug TMZ is known to increase phospholipid synthesis in cardiac membranes and to have a cardioprotective effect. Insulin deficiency was obtained by streptozotocin injection and hyperinsulinaemia was achieved via a fructose diet. Trimetazidine was incorporated into the diet (7.8 mg/day) and mitochondrial function was evaluated in skinned cardiac fibres. Insulin deficiency decreased mitochondrial affinity for ADP and the index of creatine kinase functional activity. This last alteration was partially prevented by TMZ treatment. Insulin deficiency strongly decreased n-3 polyunsaturated fatty acids, especially the docosahexaenoic acid (DHA) content, in cardiac and mitochondrial membranes, inducing a strong increase in the n-6/n-3 ratio. Trimetazidine treatment limited the increase in the n-6/n-3 ratio and prevented the decrease in DHA content in mitochondrial membranes. Insulin deficiency decreased glutamate- and palmitoylcarnitine-supported respiration. Hyperinsulinaemia affected neither mitochondrial affinity for ADP nor the index of creatine kinase functional activity. Hyperinsulinaemia slightly and significantly affected mitochondrial fatty acid composition, by a small increase the n-6/n-3 ratio. Trimetazidine did not modify membrane-bound mitochondrial function but increased the n-6/n-3 ratio. Moreover, hyperinsulinaemia decreased glutamate-supported respiration. In conclusion, modification of membrane homeostasis with TMZ partially prevented the alterations in fatty acid composition and function in cardiac mitochondria induced by insulin deficiency. Three months of hyperinsulinaemia did not modify membrane-bound mitochondrial function and had only slight effects on fatty acid composition.

Improvement of mechanical heart function by trimetazidine in db/db mice

“…These symptoms were all manifested in db/db mice, and ventricular mass did not differ among groups, consistent with the findings of a previous study[22]. The present study revealed that TMZ treatment was ineffective in treating these disease features, similar to earlier findings for STZ-induced mice[36]. Interestingly, however, blood glucose was decreased slightly in the group treated with high-dose TMZ.…”

Study of the impact of omega-3 PUFA on fatty acid composition of heart, respiration and swelling of mitochondria of the heart in diabetes

“…Îñòàíí³ì ÷àñîì äåÿê³ äîñë³äíèêè çâåðòàþòü óâàãó òàêîae íà çì³íè aeèðíîêèñëîòíîãî ñêëàäó ìåìáðàí êàðä³îì³îöèò³â ïðè ñòðåïòîçîòîöèí³íäóêîâàíîìó ÖÄ [24,28]. Íà ö³é ìîäåë³ ä³àáåòó áóëî ïðîäåìîíñòðîâàíî çíà÷íå çíèaeåííÿ âì³ñòó ω-3 ïîë³íåíà-ñè÷åíèõ aeèðíèõ êèñëîò (ÏÍAEÊ) ó ôîñôîë³-ï³äàõ ñåðöÿ ³ ïîðóøåííÿ ñï³ââ³äíîøåííÿ ω-6/ω-3 ÏÍAEÊ ó á³ê çá³ëüøåííÿ ïåðøèõ.…”

Trimetazidine Revisited: A Comprehensive Review of the Pharmacological Effects and Analytical Techniques for the Determination of Trimetazidine

“…Streptozotocin‐induced insulin deficiency decreased mitochondrial affinity for ADP, the index of creatine kinase functional activity, and decreased n‐3 polyunsaturated fatty acids in rat heart mitochondria. When TMZ was added into the diet, the decrease in creatine kinase activity and the increase in n‐6/n‐3 ratio in mitochondrial membranes were partially prevented (Ovide‐Bordeaux et al 2005). This study supported that TMZ, although partially, maintained mitochondrial homeostasis in insulin deficiency.…”