Review: A defect in the activity of Δ6 and Δ5 desaturases may be a factor in the initiation and progression of atherosclerosis
Review: A defect in the activity of Δ6 and Δ5 desaturases may be a factor in the initiation and progression of atherosclerosis
Year: 2007
Authors: Das, U.N.
Publication Name: Prostaglandins, Leukotrienes and Essential Fatty Acids
Publication Details: Volume 76; Pages 251 – 268.
Abstract:
Atherosclerosis is a dynamic process. Dyslipidemia, diabetes mellitus, hypertension, obesity, and shear stress of blood flow, the risk factors for the development of atherosclerosis, are characterized by abnormalities in the metabolism of essential fatty acids (EFAs). Gene expression profiling studies revealed that at the sites of atherosclerosis prone regions, endothelial cells showed upregulation of proinflammatory genes as well as antioxidant genes, and endothelial cells themselves showed changes in cell shape and proliferation. Uncoupled respiration (UCP1) precedes atherosclerosis at lesion-prone sites but not at the sites that are resistant to atherosclerosis. UCP1 expression in aortic smooth muscle cells causes hypertension, enhanced superoxide anion production and decreased the availability of NO, suggesting that inefficient metabolism in blood vessels causes atherosclerosis without affecting cholesterol levels. Thus, mitochondrial dysfunction triggers atherosclerosis. Atherosclerosis-free aortae have abundant concentrations of the EFA linoleate, whereas fatty streaks (an early stage of atherosclerosis) are deficient in EFAs. EFA deficiency promotes respiratory uncoupling and atherosclerosis. I propose that a defect in the activity of D6 and D5 desaturases decreases the formation of gamma linolenic acid (GLA), dihomo DGLA (DGLA), arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) from dietary linoleic acid (LA) and alpha linolenic acid (ALA). This, in turn, leads to inadequate formation of prostaglandin E1 (PGE1), prostacyclin (PGI2), PGI3,
lipoxins (LXs), resolvins, neuroprotectin D1 (NPD1), NO, and nitrolipids that have anti inflammatory and platelet anti-aggregatory actions, inhibit leukocyte activation and augment wound healing and resolve inflammation and thus, lead to the initiation and
progression atheroslcerosis. In view of this, it is suggested that D6 and D5 desaturases could serve as biological target(s) for the discovery and development of pharmaceuticals to treat atherosclerosis. (Authors abstract)
lipoxins (LXs), resolvins, neuroprotectin D1 (NPD1), NO, and nitrolipids that have anti inflammatory and platelet anti-aggregatory actions, inhibit leukocyte activation and augment wound healing and resolve inflammation and thus, lead to the initiation and
progression atheroslcerosis. In view of this, it is suggested that D6 and D5 desaturases could serve as biological target(s) for the discovery and development of pharmaceuticals to treat atherosclerosis. (Authors abstract)
In this extensive paper, the author presents an overview of the metabolism of essential fatty acids and the role of mediators of inflammation in atherosclerosis. He summarizes data which clearly show that atherosclerosis is a low-grade systemic inflammatory
condition. Mechanism(s) of the atheroprotective actions of n3 and n6 fatty acids are described. Dr. Das reviews research which identify that n3 and n6 polyunsaturated fatty acids interact with each other to prevent atherosclerosis, coronary artery disease, cardiovascular disease, and stroke, though n3 fatty acids appear to have a more dominant role compared to n6 in this beneficial action. PUFAs display a multitude of actions to prevent atherosclerosis which the authors thoroughly outline. These include positive effects on plasma lipids, on HMG-CoA reductase enzyme and on pro-inflammatory cytokines. Research is presented that indicates that atherosclerosis can be prevented/arrested if endothelial cells are able to produce adequate amounts of various PUFAs such that they in turn lead to the formation of beneficial compounds such as PGE1, PGI2, PGI3, LXs, resolvins, and nitrolipids that are capable of suppressing inflammation and the expression of various adhesion molecules on the surface of endothelial cells, and preventing leukocyte, monocyte and macrophage infiltration of endothelial cells. For the production of adequate amounts of PUFAs to occur, endothelial cells should contain appropriate activities of delta (D)6 and D5 desaturases. In view of this, Das suggests that D6 and D5 desaturases could serve as biological target(s) for the discovery and development of pharmaceuticals to treat atherosclerosis. He also stresses that an increase in tissue/cell concentrations of PUFAs, especially n3, is expected to have many beneficial actions. (Editors comments)
condition. Mechanism(s) of the atheroprotective actions of n3 and n6 fatty acids are described. Dr. Das reviews research which identify that n3 and n6 polyunsaturated fatty acids interact with each other to prevent atherosclerosis, coronary artery disease, cardiovascular disease, and stroke, though n3 fatty acids appear to have a more dominant role compared to n6 in this beneficial action. PUFAs display a multitude of actions to prevent atherosclerosis which the authors thoroughly outline. These include positive effects on plasma lipids, on HMG-CoA reductase enzyme and on pro-inflammatory cytokines. Research is presented that indicates that atherosclerosis can be prevented/arrested if endothelial cells are able to produce adequate amounts of various PUFAs such that they in turn lead to the formation of beneficial compounds such as PGE1, PGI2, PGI3, LXs, resolvins, and nitrolipids that are capable of suppressing inflammation and the expression of various adhesion molecules on the surface of endothelial cells, and preventing leukocyte, monocyte and macrophage infiltration of endothelial cells. For the production of adequate amounts of PUFAs to occur, endothelial cells should contain appropriate activities of delta (D)6 and D5 desaturases. In view of this, Das suggests that D6 and D5 desaturases could serve as biological target(s) for the discovery and development of pharmaceuticals to treat atherosclerosis. He also stresses that an increase in tissue/cell concentrations of PUFAs, especially n3, is expected to have many beneficial actions. (Editors comments)
