Mildronate, a Regulator of Energy Metabolism, Reduces Atherosclerosis in apoE/LDLR^–/– Mice

Abstract

Background/Aims: Mildronate, an inhibitor of L-carnitine biosynthesis and transport, is used in clinics as a modulator of cellular energy metabolism and is a cardioprotective drug. L-Carnitine is a pivotal molecule in fatty acid oxidation pathways and its regulation in vasculature might be a promising approach for antiatherosclerotic treatment. This study was performed to evaluate the effects of mildronate treatment on the progression of atherosclerosis and the content of L-carnitine in the vascular wall. Methods: ApoE/LDLR^–/– mice received mildronate at doses of 30 and 100 mg/kg for 4 months. Lipid profile was measured in plasma and atherosclerotic lesions were analyzed in whole aorta and aortic sinus. L-Carnitine concentration was assessed in rat aortic tissues after 2 weeks of treatment with mildronate at a dose of 100 mg/kg. Results: The chronic treatment with mildronate at a dose of 100 mg/kg significantly reduced the size of atherosclerotic plaques in the aortic roots and in the whole aorta, and slightly decreased the free cholesterol level. In addition, mildronate treatment decreased L-carnitine concentration in rat aortic tissues. Conclusions: Long-term mildronate treatment decreases L-carnitine content in aortic tissues and attenuates the development of atherosclerosis in apoE/LDLR^–/– mice.

Story behind meldonium–from pharmacology to performance enhancement: a narrative review

“…In addition, as a so-called ‘metabolic modulator,’ meldonium stimulates the synthesis of GBB, which exhibits cardioprotective activity by activating NO synthetase45 46 and attenuating endothelial dysfunction in experimental models of hypertension and atherosclerosis 45 47 48. Meldonium also preserves cardiac sarcoplasmic-reticulum Ca 2+ -ATPase and hexokinase type I in myocardial infarction, thus reducing tissue damage 26…”

Methyl-γ-butyrobetaine decreases levels of acylcarnitines and attenuates the development of atherosclerosis

“…Similarly, treating hypercholesteraemic rabbits with propionyl-Lcarnitine decreased the amount of atherosclerotic lesions [26]. In an experimental mouse model of atherosclerosis, we demonstrated that the administration of mildronate, a biosynthesis and reabsorption inhibitor of L-carnitine, decreased the amount of L-carnitine in vascular tissues and simultaneously attenuated the development of atherosclerosis [29]. More recently, a link between the dietary supplementation of L-carnitine and the accelerated development of atherosclerosis in apolipoprotein E knockout (apoE −/− ) mice has been shown [9].…”

“…This study was performed to test the effects of administering methyl-GBB, GBB and L-carnitine on the development of atherosclerosis in apoE −/− mice, as a previous study showed that lowering the L-carnitine tissue and plasma pools attenuated the development of atherosclerosis [29].…”

Gaba-betaine modulates SIRT1 and p16INK4A expression during high-glucose induced endothelial cell senescence

“…24 Indeed, results in in apoE/LDLR −/− mice model showed that decreased L-carnitine levels and increased GabaBet levels in vascular tissues are associated with anti-atherosclerotic effects. 5 Similarly, in animal model of hypertension, marked elevations of plasma GabaBet attenuate the development of endothelial dysfunction, suggesting that changes in vascular tissue levels of L-carnitine and GabaBet might have vasoprotective effects. 6 The unchanged L-carnitine content and the increased vascular levels of GabaBet counteracted the development of hGluc-induced endothelial dysfunction.…”

“…4 Indeed, previous studies indicated that mildronate, an inhibitor of carnitine biosynthesis and uptake, induces an increase in GabaBet contents and reduces atherosclerosis in apoE/LDLR −/− mice. 5 Moreover, marked elevations of GabaBet plasma levels following the administration of mildronate are associate with the improved endothelial function during hyperglycaemia and hypertension. [6][7][8] In particular, increased GabaBet levels with preserved L-carnitine content in vascular tissues attenuated the development of endothelial dysfunction induced by highglucose and had no impact on endothelial dysfunction induced by triglycerides or lysophosphatidylcholine.…”