A-family anti-inflammatory cyclopentenone prostaglandins: A novel class of non-statin inhibitors of HMG-CoA reductase
| Autor: | Helena Trevisan Schroeder, Paulo Ivo Homem de Bittencourt, Juliane da Silva Rossato, Sofia Pizzato Scomazzon, Claudia Vieira Marques, Lucila Ludmila Paula Gutierrez, João Roberto Fernandes |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Statin medicine.drug_class Anti-Inflammatory Agents Reductase Biochemistry 03 medical and health sciences chemistry.chemical_compound medicine Animals Humans Rats Wistar Cyclopentenone prostaglandins Prostaglandins A 030102 biochemistry & molecular biology biology Cell growth Cholesterol Lipid metabolism General Medicine Rats 030104 developmental biology chemistry HMG-CoA reductase biology.protein Hydroxymethylglutaryl CoA Reductases lipids (amino acids peptides and proteins) Hydroxymethylglutaryl-CoA Reductase Inhibitors Intracellular Foam Cells |
| Zdroj: | Biochimie. 182:37-50 |
| ISSN: | 0300-9084 |
| Popis: | Disruption of the intracellular lipid balance leading to cholesterol accumulation is one of the features of cells that participate in the development of atherosclerotic lesions. Evidence form our laboratory indicates that anti-inflammatory cyclopentenone prostaglandins (cyPGs) of A- and J-family deviate lipid metabolism from the synthesis of cholesterol and cholesteryl esters to the synthesis of phospholipids in foam-cell macrophages. cyPGs possessing an α,β-unsaturated cyclopentane ring are highly electrophilic substances able to promptly react with reactive cysteines of intracellular molecules through Michael addition. On the other hand, HMG-CoA reductase (HMGCR), the enzyme responsible for the rate-limiting step in cholesterol biosynthesis, presents critically reactive cysteines at the entry of catalytic domain, particularly Cys561, that could be target of cyPG inhibition. In the present study, we showed that cyPGs (but not other non-α,β-unsaturated PGs) physically interact with HMGCR, in a dithiothreitol- and β-mercaptoethanol-sensitive way, and block the activity of the catalytic subunit of the enzyme (IC50 for PGA2 = 0.17 μM). PGA2 inhibits HMGCR activity in cultured rat and human macrophages/macrophage-foam cells and leads to enhanced expression of HMGCR protein, as observed with statins. In cell culture models, PGA2 effectively inhibits the reductase at non-toxic doses (e.g., 1 μM) that block cell proliferation thus suggesting that part of the well-known antiproliferative effect of PGA2 may be due to its ability of blocking HMGCR activity, as cells cannot proliferate without a robust cholesterogenesis. Therefore, besides the powerfully anti-inflammatory and antiproliferative effects, the anticholesterogenic effects of PGA2 should be exploited in atherosclerosis therapeutics. |
| Databáze: | OpenAIRE |
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