linoleic-acid and Cardiomyopathies

Although dietary fatty acids are a major fuel for the heart, little is known about the direct effects of dietary fatty acids on gene regulation in the intact heart.. To study the effect of dietary fatty acids on cardiac gene expression and explore the functional consequences.. Oral administration of synthetic triglycerides composed of one single fatty acid altered cardiac expression of numerous genes, many of which are involved in the oxidative stress response. The gene most significantly and consistently upregulated by dietary fatty acids encoded Angiopoietin-like protein (Angptl)4, a circulating inhibitor of lipoprotein lipase expressed by cardiomyocytes. Induction of Angptl4 by the fatty acid linolenic acid was specifically abolished in peroxisome proliferator-activated receptor (PPAR)beta/delta(-/-) and not PPARalpha(-/-) mice and was blunted on siRNA-mediated PPARbeta/delta knockdown in cultured cardiomyocytes. Consistent with these data, linolenic acid stimulated binding of PPARbeta/delta but not PPARalpha to the Angptl4 gene. Upregulation of Angptl4 resulted in decreased cardiac uptake of plasma triglyceride-derived fatty acids and decreased fatty acid-induced oxidative stress and lipid peroxidation. In contrast, Angptl4 deletion led to enhanced oxidative stress in the heart, both after an acute oral fat load and after prolonged high fat feeding.. Stimulation of cardiac Angptl4 gene expression by dietary fatty acids and via PPARbeta/delta is part of a feedback mechanism aimed at protecting the heart against lipid overload and consequently fatty acid-induced oxidative stress.

Topics: alpha-Linolenic Acid; Angiopoietin-Like Protein 4; Angiopoietins; Animals; Animals, Newborn; Cardiomyopathies; Cells, Cultured; Cytoprotection; Dietary Fats; Fatty Acids, Unsaturated; Feedback, Physiological; Linoleic Acid; Lipid Peroxidation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Oleic Acid; Oxidative Stress; PPAR delta; PPAR-beta; RNA Interference; Time Factors; Up-Regulation

Here we report the identification of a previously uncharacterized human protein as the human monolysocardiolipin acyltransferase-1 (MLCL AT-1). Pig liver mitochondria were treated with n-butyl alcohol followed by Q-Sepharose chromatography, preparative gel electrophoresis, cytidine diphosphate-1,2-diacyl-sn-glycerol-Sepharose chromatography, and finally monolysocardiolipin-adriamycin-agarose affinity chromatography. Elution with either monolysocardiolipin or linoleoyl coenzyme A revealed a major band at 74 kDa with high specific activity (2,300 pmol/min/mg) for the acylation of monolysocardiolipin to cardiolipin using [1-(14)C]linoleoyl coenzyme A as substrate. Matrix-assisted laser desorption ionization time-of-flight-mass spectrometry analysis followed by search of the Mascot protein data base revealed peptide matches consistent with a 59-kDa protein identified as unknown human protein (GenBank(TM) protein accession number AAX93141; nucleotide accession number AC011742.3). The purified human recombinant MLCL AT-1 protein utilized linoleoyl coenzyme A > oleoyl coenzyme A > palmitoyl coenzyme A for the specific acylation of monolysocardiolipin to cardiolipin. Expression of MLCL AT-1 in HeLa cells increased mitochondrial monolysocardiolipin acyltransferase activity and [1-(14)C]linoleic acid incorporated into cardiolipin, whereas RNA interference knockdown of MLCL AT-1 in HeLa cells resulted in reduction in enzyme activity and [1-(14)C]linoleic acid incorporated into cardiolipin. In contrast, expression of MLCL AT-1 in HeLa cells did not alter [1-(14)C]oleic or [1-(14)C]palmitate incorporation into cardiolipin indicating in vivo specificity for the remodeling of cardiolipin with linoleate. Finally, expression of MLCL AT-1 in Barth syndrome lymphoblasts, which exhibit cardiolipin levels 20% that of normal lymphoblasts, increased mitochondrial monolysocardiolipin acyltransferase activity, [1-(14)C]linoleic acid incorporation into cardiolipin, cardiolipin mass, and succinate dehydrogenase (mitochondrial complex II) activity compared with mock-transfected Barth syndrome lymphoblasts. The results identify MLCL AT-1 as a human mitochondrial monolysocardiolipin acyltransferase involved in the remodeling of cardiolipin.

Topics: Acyltransferases; Animals; Cardiolipins; Cardiomyopathies; Computational Biology; HeLa Cells; Humans; Linoleic Acid; Lymphocytes; Mitochondria, Liver; Mitochondrial Proteins; Molecular Sequence Data; Oleic Acid; Palmitic Acid; Swine

The content of phospholipids and their fatty acid composition were followed in the hearts of two inbred strains of rats: IR, resistant against the development of isoprenaline-induced myocardial lesions and IS, sensitive to their development. In the hearts of rats of the resistant strain, a lower content of phosphatidylcholine and its plasmalogen fraction was found compared to IS rats. The total amount of phospholipids was only insignificantly lower in IR rats. Greater differences were found in individual fatty acids. The most important finding concerned lower arachidonic acid and higher linoleic acid content in heart phospholipids of IR rats. These differences were exactly opposite to changes reported in the literature in animals known to have a higher resistance against myocardial damage due to various interventions. Our results do not support the hypothesis claiming the importance of changes in phospholipids and their FA composition for the resistance of the heart against the development of necrotic lesions.

Topics: Animals; Cardiomyopathies; Fatty Acids; Isoproterenol; Linoleic Acid; Membrane Lipids; Myocardium; Norepinephrine; Phosphatidylcholines; Phospholipids; Rats; Rats, Inbred Strains

Male rats were fed for 3-4 months (short-term) or 12-15 months (long-term) on a standard laboratory diet alone (control) or supplemented with sunflower seed oil (SSO, 12% w/w) or sheep kidney fat (SKF, 12% w/w). Papillary muscles were electrically driven (1 Hz, 5 ms, supramaximal voltage) at 37 degrees C in Krebs-Henseleit solution, and contractions were measured isometrically. Both the positive inotropic responses to CA++ and the incidence of spontaneous tachyarrhythmias under catecholamine stress were increased by short-term SKF feeding and with age in control and SKF groups, whereas SSO prevented these changes. The results show a marked effect of age upon ventricular myocardial function in the rat, which appears to be accelerated by the consumption of animal (saturated) fat while polyunsaturated vegetable oil provides some degree of protection. It is suggested that changes in membrane lipid composition can alter the Ca++ handling characteristics of myocardial cells.

Topics: Age Factors; Animals; Arrhythmias, Cardiac; Blood Pressure; Calcium; Cardiomyopathies; Dietary Fats; Heart Rate; In Vitro Techniques; Isoproterenol; Linoleic Acid; Linoleic Acids; Lipidoses; Male; Myocardial Contraction; Papillary Muscles; Rats; Rats, Inbred Strains