title: Atherosclerosis: a redox-sensitive lipid imbalance suppressible by cyclopentenone prostaglandins.
abstract: Disorders concerning the metabolism of plasma and intracellular lipids are hallmarks of atherosclerosis. However, failures in proper control of intracellular cholesterol balance, rather than simple cholesterol overloading due to augmented uptake, could fuel atherogenesis. Therefore, the understanding of atherosclerosis-associated lipid alterations, which feed an inflammatory microenvironment in the arterial wall, requires the meticulous investigation of several aspects of lipid synthesis, uptake and export from cells. In this regard, the presence of reactive cysteines in transcription factors and key enzymes of lipid metabolism may dictate cholesterol accumulation, and therefore the progression of vascular disease. The strong inhibitory effect of cysteine-reactant anti-inflammatory cyclopentenone prostaglandins (CP-PGs) over atherosclerosis progression in vivo (LipoCardium technology) symbolizes a new concept of atherosclerosis and its treatment. Results from this laboratory and those from other research groups have unraveled a novel facet in prostaglandin research in that CP-PGs may act as redox signals that guide lipid metabolism in atherosclerosis. By modifying enzymes (e.g., HMG-CoA reductase, ACAT and cholesteryl ester hydrolases) and transcription factors (e.g., NF-kappaB and Keap1) involved in inflammation and lipid metabolism, CP-PGs (especially those of A-series) induce pivotal changes in glutathione and lipid metabolism that completely arrest atherosclerosis progression. Hence, pharmacological manipulation of lipid metabolism by CP-PGs may be a novel and invaluable strategy for treating atherosclerosis. Also, a better understanding of why CP-PGs do not resolve inflammation physiologically may explain many unsolved questions and yield insights into atherogenesis and its termination.
authors.affiliation: Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, 90050-170 Porto Alegre, RS, Brazil.
authors.forename: Lucila Ludmila Paula
authors.initials: LL
authors.lastname: Gutierrez
authors.forename: Alexandre
authors.initials: A
authors.lastname: Maslinkiewicz
authors.forename: Rui
authors.initials: R
authors.lastname: Curi
authors.forename: Paulo Ivo Homem
authors.initials: PI
authors.lastname: de Bittencourt
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D050197:Atherosclerosis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis; D003517:Cyclopentanes / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D050356:Lipid Metabolism / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010084:Oxidation-Reduction; D011453:Prostaglandins / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology; D011485:Protein Binding
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003517:Cyclopentanes; D008024:Ligands; D011453:Prostaglandins; C007201:cyclopentanone; D002784:Cholesterol