Unhealthy diet and ultrafine carbon black particles induce senescence and disease associated phenotypic changes
Unhealthy diet and ultrafine carbon black particles induce senescence and disease associated phenotypic changes
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DOI：
10.1016/j.exger.2012.03.017
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发表时间：
2013-01-01
影响因子：
3.9
通讯作者：
Haendeler, Judith
中科院分区：
文献类型：
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作者：
Buechner, Nicole;Ale-Agha, Niloofar;Haendeler, Judith
饮食和污染是已知会损害心血管和呼吸系统“健康衰老”的环境因素。这些细胞中这种永久负担的分子后果仍然未知。因此，本研究探讨了不健康饮食对人类、初级心血管细胞以及空气中颗粒对肺上皮和人内皮细胞的衰老相关信号通路的影响。营养健康报告显示，工业化国家的饮食中含有超过 100 毫克/分升的低密度脂蛋白 (LDL) 和大量添加糖，尤其是果糖。多项研究表明，超细颗粒可以进入循环系统，因此可能直接与内皮细胞相互作用。膳食化合物和污染源颗粒均已被证明会增加心血管疾病的风险。为了模拟不健康的饮食，我们在人原代内皮细胞、平滑肌细胞和心肌细胞的细胞培养基中添加了LDL，并用果糖代替了1/3的葡萄糖。我们观察到心肌细胞肥大、平滑肌细胞增殖增强、衰老增加、内皮一氧化氮合酶丧失以及内皮细胞核 FoxO3A 增加。在污染方面，我们使用了超细炭黑颗粒 (ufCB)，它是工业和废气排放的主要成分之一，其浓度是我们的肺部和血管经常暴露的浓度。这些浓度的 ufCB 增加了肺上皮细胞和血管内皮细胞中的活性氧，并降低了内皮细胞中的 S-NO 含量（NO 生物利用度的标志物）。 NO 会增加端粒酶逆转录酶 (TERT) 的激活，TERT 是端粒维持所必需的酶。 TERT 是内皮细胞正常功能所必需的，并且在氧化应激条件下会被 Src 激酶失活。 ufCB 显着增加内皮细胞和肺上皮细胞中 Src 激酶的激活并降低端粒酶的活性。结果，ufCB 增加了内皮细胞的衰老。为了研究 ufCB 是否也显示出体内作用，我们将不引起炎症的浓度的 ufCB 滴注到小鼠体内。事实上，用 ufCB 治疗的动物的腹主动脉中 eNOS 表达减少。因此，饮食中的果糖和 LDL 以及 ufCB 作为空气污染的主要成分的组合似乎会加速呼吸和心血管细胞的变化，这可能会损害“健康衰老”，并可能导致心血管和肺部疾病。 (C) 2012 Elsevier Inc. 保留所有权利。
Diet and pollution are environmental factors known to compromise "healthy aging" of the cardiovascular and respiratory systems. The molecular consequences of this permanent burden in these cells are still unknown. Therefore, this study investigates the impact of unhealthy diet on aging-related signaling pathways of human, primary cardiovascular cells and of airborne particles on lung epithelial and human endothelial cells. Nutrition health reports have shown that the diet in industrialized countries contains more than 100 mg/dl low density lipoprotein (LDL) and a high fraction of added sugars, especially fructose. Several studies demonstrated that ultrafine particles can enter the circulation and thus may interact with endothelial cells directly. Both, dietary compounds and pollution derived particles, have been shown to increase the risk for cardiovascular diseases. To simulate an unhealthy diet, we supplemented cell culture media of human primary endothelial cells, smooth muscle cells and cardiomyocytes with LDL and replaced 1/3 of glucose with fructose. We observed hypertrophy in cardiomyocytes, enhanced proliferation in smooth muscle cells and increased senescence, loss of endothelial nitric oxide synthase and increased nuclear FoxO3A in endothelial cells. With respect to pollution we have used ultrafine carbon black particles (ufCB), one of the major constituents of industrial and exhaust emissions, in concentrations our lungs and vessels are constantly exposed to. These concentrations of ufCB increased reactive oxygen species in lung epithelial and vascular endothelial cells and reduced the S-NO content, a marker for NO-bioavailability, in endothelial cells. NO increases activation of Telomerase Reverse Transcriptase (TERT), an enzyme essential for telomere maintenance. TERT is required for proper endothelial cell function and is inactivated by Src kinase under conditions of oxidative stress. ufCB significantly increased Src kinase activation and reduced Telomerase activity in endothelial and lung epithelial cells. As a consequence, ufCB increased senescence of endothelial cells. To investigate whether ufCB show also effects in vivo, we instilled ufCB in concentrations not inducing inflammation into mice. Indeed, eNOS expression was reduced in the abdominal aorta of animals treated with ufCB.Thus, a combination of fructose and LDL in the diet and ufCB, as a major constituent of air pollution, seem to accelerate respiratory and cardiovascular cellular changes, which may compromise "healthy aging" and can lead to cardiovascular and pulmonary diseases. (C) 2012 Elsevier Inc. All rights reserved.