Oxidative stress induces endothelial cell senescence via downregulation of Sirt6.
Oxidative stress induces endothelial cell senescence via downregulation of Sirt6.
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DOI：
10.1155/2014/902842
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发表时间：
2014
影响因子：
--
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Liu R;Liu H;Ha Y;Tilton RG;Zhang W
越来越多的证据表明，糖尿病加速衰老，内皮细胞衰老参与糖尿病血管并发症的发病机制，包括糖尿病视网膜病变。氧化应激被认为是诱导内皮细胞衰老和糖尿病视网膜病变的关键因素。然而，氧化应激诱导内皮细胞衰老的具体机制尚未阐明。我们假设Sirt6可能在氧化应激诱导的血管细胞衰老中起作用，Sirt6是一种核染色质结合蛋白，它在许多病理生理过程（如衰老和炎症）中起关键作用。在人内皮细胞中Sirt6表达的测量显示H2O2处理显著降低Sirt6蛋白。Sirt6的缺失与内皮细胞衰老表型的诱导有关，包括细胞生长、增殖和血管生成能力的降低，以及衰老相关β-半乳糖苷酶活性的表达增加。此外，H2O2处理降低eNOS表达，增强p21表达，并使视网膜母细胞瘤（Rb）蛋白去磷酸化（活化）。所有这些变化都通过过表达Sirt6而减弱，而siRNA部分敲低Sirt6的表达类似H2O2的作用。总之，这些结果表明Sirt6是内皮细胞衰老的关键调节因子，氧化应激诱导的Sirt6下调可能参与了糖尿病视网膜病变的发病机制。
Accumulating evidence has shown that diabetes accelerates aging and endothelial cell senescence is involved in the pathogenesis of diabetic vascular complications, including diabetic retinopathy. Oxidative stress is recognized as a key factor in the induction of endothelial senescence and diabetic retinopathy. However, specific mechanisms involved in oxidative stress-induced endothelial senescence have not been elucidated. We hypothesized that Sirt6, which is a nuclear, chromatin-bound protein critically involved in many pathophysiologic processes such as aging and inflammation, may have a role in oxidative stress-induced vascular cell senescence. Measurement of Sirt6 expression in human endothelial cells revealed that H2O2 treatment significantly reduced Sirt6 protein. The loss of Sirt6 was associated with an induction of a senescence phenotype in endothelial cells, including decreased cell growth, proliferation and angiogenic ability, and increased expression of senescence-associated β-galactosidase activity. Additionally, H2O2 treatment reduced eNOS expression, enhanced p21 expression, and dephosphorylated (activated) retinoblastoma (Rb) protein. All of these alternations were attenuated by overexpression of Sirt6, while partial knockdown of Sirt6 expression by siRNA mimicked the effect of H2O2. In conclusion, these results suggest that Sirt6 is a critical regulator of endothelial senescence and oxidative stress-induced downregulation of Sirt6 is likely involved in the pathogenesis of diabetic retinopathy.
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DOI：
10.1073/pnas.1314575110
发表时间：
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影响因子：
11.1
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