Hyperlipidemia-induced cholesterol crystal production by endothelial cells promotes atherogenesis
| Autor: | Sara McCurdy, Noboru Yamazaki, Yvonne Baumer, Stefan J. Halbherr, William A. Boisvert, Tina M. Weatherby, Nehal N. Mehta, Pascal Halbherr |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Apolipoprotein E Male General Physics and Astronomy 030204 cardiovascular system & hematology chemistry.chemical_compound Mice 0302 clinical medicine Hyperlipidemia lcsh:Science Barrier function Aorta Cells Cultured Multidisciplinary Forskolin Chemistry food and beverages 3. Good health Femoral Artery Lipoproteins LDL medicine.anatomical_structure Carotid Arteries Cholesterol Female lipids (amino acids peptides and proteins) Rolipram medicine.drug medicine.medical_specialty Endothelium Science Hyperlipidemias Mice Transgenic Diet High-Fat General Biochemistry Genetics and Molecular Biology Article Apolipoproteins E 03 medical and health sciences Internal medicine medicine Animals Humans Colforsin fungi Endothelial Cells General Chemistry Sinus of Valsalva medicine.disease Atherosclerosis Mice Inbred C57BL 030104 developmental biology Endocrinology Liposomes lcsh:Q Endothelium Vascular |
| Zdroj: | Nature Communications, Vol 8, Iss 1, Pp 1-14 (2017) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Endothelial cells (EC) play a key role in atherosclerosis. Although EC are in constant contact with low density lipoproteins (LDL), how EC process LDL and whether this influences atherogenesis, is unclear. Here we show that EC take up and metabolize LDL, and when overburdened with intracellular cholesterol, generate cholesterol crystals (CC). The CC are deposited on the basolateral side, and compromise endothelial function. When hyperlipidemic mice are given a high fat diet, CC appear in aortic sinus within 1 week. Treatment with cAMP-enhancing agents, forskolin/rolipram (F/R), mitigates effects of CC on endothelial function by not only improving barrier function, but also inhibiting CC formation both in vitro and in vivo. A proof of principle study using F/R incorporated into liposomes, designed to target inflamed endothelium, shows reduced atherosclerosis and CC formation in ApoE −/− mice. Our findings highlight an important mechanism by which EC contribute to atherogenesis under hyperlipidemic conditions. Atherosclerosis is characterized by subendothelial lipid retention believed to be the result of endothelial trancytosis. Here, the authors show that endothelium can take up and process LDL, generating cholesterol crystals that are deposited on the basolateral side of the cells, causing their dysfunction that can be prevented by forskolin/rolipram treatment. |
| Databáze: | OpenAIRE |
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