Abstract 363: Lysosomal Lipid Accumulation and Dysregulation of Downstream Cholesterol Homeostasis in Human Arterial Smooth Muscle Cells
| العنوان: | Abstract 363: Lysosomal Lipid Accumulation and Dysregulation of Downstream Cholesterol Homeostasis in Human Arterial Smooth Muscle Cells |
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| المؤلفون: | Joshua A Dubland, Collin S Pryma, Sima Allahverdian, Ying Wang, Teddy Chan, Gordon A Francis |
| المصدر: | Arteriosclerosis, Thrombosis, and Vascular Biology. 37 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine |
| الوصف: | Background and Hypothesis: Previously we reported that ≥ 50% of the foam cells in human coronary artery atherosclerosis are smooth muscle cell (SMC) derived, and that the rate-limiting cholesterol exporter, ATP-binding cassette transporter protein A1 (ABCA1), has reduced expression in SMCs compared to leukocytes in the intima. Upregulation of ABCA1 expression is dependent on normal flux of lipoprotein-derived cholesterol out of lysosomes and the subsequent generation of 27-hydroxycholesterol (27-OHC). Excess lipoprotein-derived cholesterol is also converted to cholesteryl esters (CE) through the actions of acyl-coA cholesterol acyltransferase (ACAT). Processes by which macrophages store lipoprotein-derived cholesterol in cytosolic and lysosomal compartments are well described, whereas less is known about SMCs. Hypothesis: We hypothesize that preferential SMC foam cell formation and the observed derangement in ABCA1 expression are associated with increased lysosomal sequestration of atherogenic lipids. Methods and Results: Human aortic SMCs and human monocyte-derived macrophages (HMMs) were loaded with aggregated LDL (agLDL) for 24 hrs, followed by a 24 hr equilibration without lipids to allow processing of lipoproteins. Data are presented as mean±SEM. In response to agLDL, CE content (nmol/mg protein) measured by LC/MS/MS increased from 2.2±1.3 to 277.0±18.2 in HMMs, and 3.5±5.3 to 46.8±14.5 in SMCs (n=9). Confocal microscopy indicated elevated lysosomal lipid accumulation in SMCs compared to HMMs. Levels of 27-OHC (ng/mg protein) as measured by LC/MS/MS increased from 80.9±9.5 to 281.4±22.7 (3.5-fold) in HMMs, and 0.7±0.2 to 1.5±0.3 (1.4-fold) in SMCs (n=9). ACAT activity, measured by the incorporation of 14 C-labelled oleate (pmol/mg protein), increased from 21.0±1.7 to 678.1±110.9 (32.2-fold) in HMMs, and 55.6±3.3 to 133.7±15.2 (2.4-fold) in SMCs (n=16). By Western blot, fold change in ABCA1 with exposure to agLDL was 2.3±0.3 in HMMs and 1.3±0.2 in SMCs (n=7-10). Conclusions: Accumulation of atherogenic lipids in the lysosomes of SMCs provides a potential mechanism for the reduced ABCA1 expression and preferential formation of foam cells by arterial SMCs. |
| تدمد: | 1524-4636 1079-5642 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::bb3f68c8643da98f83a431e2b3389f80 https://doi.org/10.1161/atvb.37.suppl_1.363 |
| رقم الأكسشن: | edsair.doi...........bb3f68c8643da98f83a431e2b3389f80 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244636 10795642 |
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