Vascular Pathology and Experimental Nephrology Laboratory, Fundación Jiménez Díaz/Autonoma University/IRSIN, Madrid, Spain.
Diabetes. 2010 Jun;59(6):1292-301. doi: 10.2337/db09-0848. Epub 2010 Mar 3.
Atherosclerosis is prevalent in diabetic patients, but there is little information on the localization of nonesterified fatty acids (NEFAs) within the plaque and their relationship with inflammation. We sought to characterize the NEFA composition and location in human diabetic atheroma plaques by metabolomic analysis and imaging and to address their relationship with inflammation activity.
Time-of-flight secondary ion mass spectrometry (TOF-SIMS) was used for metabolomic analysis imaging of frozen carotid atheroma plaques. Carotid endarterectomy specimens were used for conventional immunohistochemistry, laser-capture microdissection quantitative PCR, and in situ Southwestern hybridization. Biological actions of linoleic acid were studied in cultured vascular smooth muscle cells (VSMCs).
TOF-SIMS imaging evidenced a significant increase in the quantity of several NEFA in diabetic versus nondiabetic atheroma plaques. Higher levels of NEFA were also found in diabetic sera. The presence of LPL mRNA in NEFA-rich areas of the atheroma plaque, as well as the lack of correlation between serum and plaque NEFA, suggests a local origin for plaque NEFA. The pattern of distribution of plaque NEFA is similar to that of MCP-1, LPL, and activated NF-kappaB. Diabetic endarterectomy specimens showed higher numbers of infiltrating macrophages and T-lymphocytes-a finding that associated with higher NEFA levels. Finally, linoleic acid activates NF-kappaB and upregulates NF-kappaB-mediated LPL and MCP-1 expression in cultured VSMC.
There is an increased presence of NEFA in diabetic plaque neointima. NEFA levels are higher in diabetic atheroma plaques than in nondiabetic subjects. We hypothesize that NEFA may be produced locally and contribute to local inflammation.
糖尿病患者中动脉粥样硬化较为常见，但有关斑块内非酯化脂肪酸（NEFA）的定位及其与炎症的关系的信息较少。我们试图通过代谢组学分析和成像来描述人糖尿病动脉粥样硬化斑块中 NEFA 的组成和定位，并探讨其与炎症活动的关系。
采用飞行时间二次离子质谱（TOF-SIMS）对冷冻颈动脉粥样硬化斑块进行代谢组学分析成像。使用颈动脉内膜切除术标本进行常规免疫组织化学、激光捕获显微切割定量 PCR 和原位西南杂交。在培养的血管平滑肌细胞（VSMCs）中研究亚油酸的生物学作用。
TOF-SIMS 成像表明，与非糖尿病动脉粥样硬化斑块相比，糖尿病动脉粥样硬化斑块中几种 NEFA 的数量显著增加。糖尿病患者的血清中也发现了更高水平的 NEFA。动脉粥样硬化斑块中富含 NEFA 的区域存在 LPL mRNA，以及血清和斑块 NEFA 之间缺乏相关性，提示斑块 NEFA 具有局部来源。斑块 NEFA 的分布模式与 MCP-1、LPL 和激活的 NF-kappaB 相似。糖尿病内膜切除术标本显示浸润的巨噬细胞和 T 淋巴细胞数量增加，这与更高的 NEFA 水平有关。最后，亚油酸激活 NF-kappaB，并上调培养的 VSMC 中 NF-kappaB 介导的 LPL 和 MCP-1 表达。
糖尿病斑块新生内膜中存在更多的 NEFA。糖尿病动脉粥样硬化斑块中的 NEFA 水平高于非糖尿病患者。我们假设 NEFA 可能在局部产生，并有助于局部炎症。
