Fatty acids as sources of potential “magic bullets” for the modification of platelet and vascular function
Abstract
Platelet cyclooxygenase exhibits a pronounced structural specificity whereas the lipoxygenase does not. Agonist recognition by platelets appears to be highly discriminatory. Endoperoxides apparently act on different receptors than do the thromboxanes and furthermore, thromboxane receptor recognition and/or activation must differ in blood vessels and platelets. The α-chain of the fatty acid metabolites profoundly influences receptor recognition without apparent influence of substrate affinity by the synthetic enzymes. The availability of inactive products or of partial agonists for the vascular and platelet receptors could lead to the development of selective receptor agonists and antagonists. Obviously there would be a considerable advantage in developing platelet-specific receptor analogs which do not influence smooth muscle receptors.
Fatty acids which possess a unsaturation are readily converted by a calcium-dependent, cell-free enzyme system into mono- and dihydroxy fatty acids. However, in the presence of glutathione, this enzyme system completely assembles the biologically active slow-reacting substance of anaphylaxis (now termed leukotrienes C and D). Thus, arachidonic acid (5, 8, 11, 14), eicosapentaenoic acid (5, 8, 11, 14, 17), and 20:3 (5, 8, 11; which accumulates during essential fatty acid deficiency) all are excellent substrates for the synthesis of potent biologically active leukotrienes.
Eicosapentaenoic acid (EPA, 5, 8, 11, 14, 17-) can serve as a prototype for the utilization of a fatty acid as a dietary strategy for the manipulation of certain disease processes. EPA as well as other members of the ω3 fatty acid family are effective antagonists of arachidonic acid metabolism (both exogenous or endogenous) by platelet cyclooxygenase. A substitution of EPA or possibly its precursor (9, 12, 15-octadecatrienoic acid, α-linolenic acid) in the diet would be expected to lead to both an inhibition of arachidonic acid metabolism and the lowering of endogenous arachidonate in tissue (e.g., platelets) lipids. The net anticipated result would be a marked reduction in the generation of PGH2 and thromboxane A2 which cause platelet aggregation. A preliminary clinical trial supporting this hypothesis has recently appeared. However, the discovery of the ease of conversion of EPA into the bronchoconstrictor leukotrienes demands appropriate caution and additional experimentation prior to widespread dietary supplementation.
References (14)
- J. Dyerberg et al.
Lancet
(1979) - J. Dyerberg et al.
Lancet
(1978) - B.A. Jakschik et al.
Biochem. Biophys. Res. Commun.
(1980) - B.A. Jakschik et al.
Prostaglandins
(1980) - P. Needleman et al.
Prostaglandins
(1980) - W. Siess et al.
Lancet
(1980) - B.A. Jakschik et al.
Nature
(1980)
Cited by (21)
The effect of different dietary lipid supplements on the nonesterified fatty acid composition of normoxic rat hearts: A link between nutrition and cardiac arrhythmia
1992, Nutrition ResearchIn addition to changes in the fatty acid composition of cardiac membrane phospholipids, alterations in the dietary lipid intake of rats influence the composition but not the amount of myocardial nonesterified fatty acids (NEFA's). These changes are apparent in the relative proportions of arachidonic acid (AA) and those other polyunsaturated fatty acids (PUFA's) such as linoleic acid (LA) or docosahexaenoic acid (DHA) which are either substrates for or competitive inhibitors of the conversion of AA to the 2-series eicosanoids. In particular changes in the relative proportions of AA, LA and DHA in myocardial NEFA are associated with alterations in the production of myocardial thromboxane (TXA2) and the vulnerability of the heart to develop arrhythmia during partial ischaemia. These results suggest a link between the type of dietary fat intake, the composition of myocardial NEFA and the development of the lethal arrhythmias which are responsible for Sudden Cardiac Death.
Arachidonic acid and linoleic acid supplementation increase prostanoid production in rats fed a butter-enriched diet
1990, Prostaglandins, Leukotrienes and Essential Fatty AcidsMale Sprague Dawley rats were fed a butter-enriched diet (50% fat) for 2 weeks and then supplemented orally with either 90 mg of ethyl arachidonate or ethyl linoleate daily for 2 weeks. For comparative reasons, one group of animals was fed standard laboratory rat chow for 4 weeks. Aortic prostacyclin (PGI2) production, platelet aggregation and thromboxane A2 (TXA2) production and plasma and aortic phospholipid (PL) fatty acids were measured. When compared to butter-fed rats, aortic PGI2 production, collagen-induced platelet aggregation and TXA2 production were significantly increased in rats supplemented with ethyl arachidonate to levels similar to those seen in chow-fed rats. Ethyl linoleate supplementation also tended to increase aortic PGI2 production, collagen-induced platelet aggregation and TXA2, but not to the same extent. These changes were accompanied by increases in the level of arachidonic acid and linoleic acid in aortic and plasma PL and a decrease in the level of eicosapentaenoic acid (EPA) and docsahexaenoic acid (DHA). These data indicate that supplementation with small doses of preformed arachidonic acid was more effectie than supplementation with its precursor, linoleic acid, in reversing the effects on prostanoid production and phospholipid fatty acid composition in rats fed diets enriched with butter.
Substrate specificity of the agonist-stimulated release of polyunsaturated fatty acids from vascular endothelial cells
1989, Archives of Biochemistry and BiophysicsStimulation of vascular endothelial cells with agonists such as histamine and thrombin results in release of arachidonic acid from membrane lipids and subsequent eicosanoid synthesis. As shown previously, the agonist-stimulated deacylation is specific for arachidonate, eicosapentaenoate, and 5,8,11-eicosatrienoate. This study has utilized radiolabeled fatty acids differing in chain length and position of double bonds to further elucidate the fatty acyl specificity of agonist-stimulated deacylation. Replicate wells of confluent human umbilical vein endothelial cells were incubated with 14C-labeled fatty acids and then challenged with histamine, thrombin, or the calcium ionophore A23187. Comparison of the results obtained with isomeric eicosatetraenoic fatty acids with initial double bonds at carbons 4, 5, or 6 indicated that the deacylation induced by all three agonists exhibited marked specificity for the cis-5 double bond. Lack of stringent chain length specificity was indicated by agonist-stimulated release of 5,8,11,14-tetraenoic fatty acids with 18, 19, 20, and 21 carbons. Release of 5,8,14-[14C]eicosatrienoate was two-to threefold that of 5,11,14-[14C]eicosatrienoate, thus indicating that the cis-8 double bond may also contribute to the stringent recognition by the agonist-sensitive phospholipase. The present study has also demonstrated that histamine, thrombin, and A23187 do not stimulate release of docosahexaenoate from endothelial cells.
Dissimilar fatty acid composition of standard rat chow
1989, American Journal of the Medical SciencesThe lower incidence of coronary heart disease in populations consuming polyunsaturated fatty acids has spurred interest in the possible cardioprotective nature of these fatty acids. Furthermore, the source of dietary fats may modify the natural history of some chronic inflammatory disorders such as rheumatoid arthritis and systemic lupus erythematosus. Some studies examining these issues have involved animals fed a standard chow diet to which the desired fatty acids were added” Our observation that two lots of standard rat chow varied considerably in fatty acid composition, prompted us to analyze two additional standard rat chow lots for fatty acid composition. Each lot was extracted and fatty acid chain ‘length determined by gas chromatography with the percentage of total: fatty acids determined by integration. A wide variation in the total saturated (27.4–42.1%), monounsaturated (8.3–30.9%), omega 6 (17.2–44.2%), and omega 3 (3.8–11.2%) fatty acids was observed. By one-way analysis of variance, significant differences (p < 0.025) between the various lots were observed for total saturated, monounsaturated, and omega 6 fatty acid groups. These findings suggest that fatty acid composition of standard rat chow is not similar. If the baseline fatty acid composition is critical to the experimental design, custom chow diets should be used.
Low platelet apachidonic acid in young patients with brain infarction
1987, Thrombosis ResearchFatty acid patterns of plasma and platelet lipids, platelet aggregation and thromboxane A2(TxA2) production were studied in young patients (n = 12) with brain infarction and in healthy controls (n = 13). Platelet arachidonic acid content was significantly reduced in the stroke patients, but in vitro platelet aggregation was similar in the two groups. A low dose of acetosalicylic acid (ASA) (100 mg) suppressed thromboxane production and normalized the platelet arachidonic acid values. The low arachidonic acid in platelets is probably due to its increased consumption, indicating platelet activation in vivo.
Long-term saturated fat supplementation in the rat causes an increase in PGI<inf>2</inf> TXB<inf>2</inf> ratio of platelet and vessel wall compared to n - 3 and n - 6 dietary fatty acids
1987, AtherosclerosisThe effect of long-term manipulation of dietary lipid intake on platelet and vessel wall lipid composition and eicosanoid synthesis was investigated. Rats were fed a standard diet (REF diet) supplemented (12% w/w) with either sheep fat (SF), sunflower seed oil (SSO) or tuna fish oil (TFO) for a period of 15 months. Significant compositional changes both in the aorta and platelets were observed following dietary lipid treatment and differences between these tissues were particularly apparent with regard to the incorporation and conversion of n − 3 fatty acids. For example, platelets displayed a selective accumulation of eicosapentaenoic acid (EPA, 20: 5 n − 3) over docosahexaenoic acid (DHA, 22: 6, n − 3), but in the aorta the proportion of DHA was considerably higher than that of EPA. In both tissues, compared to REF diet, n − 3 dietary fatty acids replaced the n − 6 unsaturates 20: 4 and 22: 4, but did not affect the proportion of linoleic acid. In contrast to aorta, the unsaturation index for platelet membrane varied significantly between dietary groups.
The capacity of aorta and platelets to generate PGI2-like activity and thromboxane was unaltered by the SSO diet. However, changes were seen following SF and TFO supplementation. Rats fed the SF diet displayed a greater synthetic capacity whilst in animals maintained on TFO diet the synthesis of these two eicosanoids was considerably suppressed. The SF group displayed the highest value for PGI2/TXB2 ratio whereas TFO diet fed rats showed the lowest which may partly be due to synthesis of TXA3. The reduction in eicosanoids following the tuna fish oil supplementation can be explained on the basis of concurrent compositional changes. Conversely, the increase in eicosanoids in the SF group may perhaps reflect a compensatory mechanism peculiar to the rat, although alterations in eicosanoid synthetic enzyme themselves cannot be ruled out.