Shi Qiang, Hornsby Peter J, Meng Qinghe, Vandeberg Jane F, Vandeberg John L
Southwest National Primate Research Center, Texas Biomedical Research Institute P.O. Box 760549, San Antonio, Texas, TX 78245.
Am J Cardiovasc Dis. 2013 Aug 16;3(3):107-19. eCollection 2013.
A high-fat diet is a major risk factor for atherosclerosis. We conducted a longitudinal investigation to determine whether vascular endothelial senescence is involved in the mechanism by which a high-fat diet promotes atherogenesis. We challenged 10 baboons (Papio sp.) with a high-cholesterol high-fat (HCHF) diet for 7 weeks. In addition to multiple changes in plasma lipid profiles, inflammatory status, and endothelial functions in each individual, we found that levels of total serum cholesterol (TSC) and monocyte chemotactic protein-1 (MCP-1) were negatively and significantly correlated with endothelial nitric oxide synthase (eNOS) levels in endothelial cells while the levels of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were significantly correlated with nitric oxide levels in plasma within this time window. Most important, we observed that senescence-associated β-galactosidase (SA-β-gal) activities in endothelial cells harvested at 7 weeks after initiation of HCHF diet were significantly elevated by comparison with cells isolated from the same animals prior to dietary challenge. The SA-β-gal activities correlated significantly with the elevations of TSC, LDL-cholesterol, HDL-cholesterol, and IL-8 after 7 weeks of HCHF diet and with the changes of TSC and TNF-α levels after 3 weeks of HCHF diet. Our data indicate that the HCHF diet caused hyperlipidemia and prominent inflammation, which subsequently will cause endothelial dysfunction and promote senescence. The present study is the first to demonstrate the sequential and interactive changes as a consequence of an HCHF dietary challenge and establish a potential mechanism underlying the etiology of diet-induced atherogenesis in a nonhuman primate.
高脂饮食是动脉粥样硬化的主要危险因素。我们进行了一项纵向研究，以确定血管内皮衰老是否参与高脂饮食促进动脉粥样硬化形成的机制。我们用高胆固醇高脂肪（HCHF）饮食对10只狒狒（Papio sp.）进行了7周的挑战。除了每只动物的血浆脂质谱、炎症状态和内皮功能发生多种变化外，我们发现血清总胆固醇（TSC）和单核细胞趋化蛋白-1（MCP-1）水平与内皮细胞中的内皮型一氧化氮合酶（eNOS）水平呈显著负相关，而肿瘤坏死因子α（TNF-α）和白细胞介素6（IL-6）水平与该时间窗内血浆中的一氧化氮水平显著相关。最重要的是，我们观察到，与饮食挑战前从同一动物分离的细胞相比，在开始HCHF饮食7周后收获的内皮细胞中衰老相关β-半乳糖苷酶（SA-β-gal）活性显著升高。SA-β-gal活性与HCHF饮食7周后TSC、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇和IL-8的升高以及HCHF饮食3周后TSC和TNF-α水平的变化显著相关。我们的数据表明，HCHF饮食导致高脂血症和显著炎症，随后将导致内皮功能障碍并促进衰老。本研究首次证明了HCHF饮食挑战导致的一系列相互作用的变化，并在非人类灵长类动物中建立了饮食诱导动脉粥样硬化病因的潜在机制。
