Carnitine System: a Tool for Understanding Functioning and Dysfunctioning Cardiovascular Apparatus
Benatti P.1, Reda E.1, Nicolai R.1, Peluso G.2, and Calvani M.2.
1Scientific Department, Sigma Tau S.p.A., via Pontina Km 30,400, Pomezia, Rome, 22nd University of Naples, piazza Miraglia, Naples, Italy
Carnitine is a small water-soluble molecule widely distributed in nature and highly concentrated in the human heart. Carnitine is synthetized by liver and kidney, and to a lesser extent by brain, but the greatest source is the diet. Carnitine is the specific substrate of a network of enzymes present in almost all the subcellular organelles. In all mammalian cells, the carnitine system is one of the machineries that make possible substrate regulation of genes in response to the nutritional environment. Cells utilize the carnitine system mainly to intermediate glucose and lipid metabolism. The components of this system, carnitine itself, acylcarnitines, and the enzymic network, various carnitine acyltransferases and carnitine translocase, intervene in the utilization of substrates for energy production at the mitochondrial and peroxisomal level, and the transport of acyl groups across other cellular membranes for synthesis purposes, membrane maintenance and repair (acyl trafficking). The function of the carnitine system is also extended to the nucleus where it modulates the intranuclear fatty acyl-CoA levels, thus the system feeds information back to the nucleus, possibly influencing the fatty acid mediated control of gene transcription. There are tissue different carnitine concentrations, different roles for some short-chain acylcarnitine esters, and different functional properties and expression of the enzymes belonging to the carnitine system, which account for the organ specific metabolic purposes. A peculiar complexity of the carnitine system is at the base of optimal cardiac functioning to transform metabolic energy in mechanical work. Carnitine and its enzyme network are fully involved in the management of metabolic derangement when substrates such as glucose and fatty acids present abnormally. Conditions such as dyslipidemia and insulin resistance exemplified this involvement. Conversely, these metabolic conditions may arise when carnitine concentrations and/or its enzyme network are abnormal, i.e., carnitine deficiency or carnitine insufficiency (genetic and acquired forms). In both cases, the cardiovascular system is fundamentally implicated with myocardial and /or vascular dysfunction, and with changes in the cardiac phenotype expression of the carnitine machinery (i.e., enzyme isoform expression). Several evidences demonstrated that patients under treatment with certain drugs (i.e. adriamycin, pivalic acid) present with myocardial carnitine insufficiency due to drug-exerted toxic effects on carnitine enzymes or to drug-induced deficiency of carnitine. Furthermore, pathologies such as myocardial hypertrophy, ischemia, heart failure, and vascular atherosclerosis, induce depauperation of carnitine levels and modifications in the carnitine/acylcarnitine ratio which indicates that the pathology results in an unbalancing of the carnitine system. At present, molecular biology is a tool to observe the carnitine system which may represent a biomarker of dysmetabolism characterizing cardiovascular disease. In all cases, carnitine or its esters supplementation improves cardiovascular performance by influencing the carnitine system itself and restoring the physiological carnitines pool.