2013 Russell Ross memorial lecture in vascular biology: cellular and molecular mechanisms of diabetes mellitus-accelerated atherosclerosis.
2013 Russell Ross memorial lecture in vascular biology: cellular and molecular mechanisms of diabetes mellitus-accelerated atherosclerosis.
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DOI：
10.1161/atvbaha.113.301928
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发表时间：
2014-04
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影响因子：
--
通讯作者：
Bornfeldt KE
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作者：
Bornfeldt KE
患有糖尿病的成年人比没有糖尿病的成年人更容易患心血管疾病。基因工程小鼠模型已开始为糖尿病促进动脉粥样硬化的机制提供重要的见解。这些模型已经证明，糖尿病促进动脉粥样硬化病变的形成、病变进展为晚期出血病变，并且它防止病变消退。糖尿病的促动脉粥样硬化作用部分是由骨髓细胞功能的改变引起的。蛋白质 S100A9 和晚期糖基化终产物受体是糖尿病对骨髓细胞生成影响的重要介质。此外，髓样细胞表达酰基辅酶A合成酶1（ACSL1），该酶可将长链脂肪酸转化为其酰基辅酶A衍生物，已成为糖尿病诱发病变起始的原因。 S100A9 缺陷和骨髓 ACSL1 缺陷对糖尿病小鼠的保护作用（但对非糖尿病小鼠则不然）表明，糖尿病通过在不存在糖尿病的情况下发挥次要作用的机制来激活骨髓细胞。还讨论了活性氧和胰岛素抵抗在糖尿病加速的动脉粥样硬化中的作用，主要与内皮细胞有关。解决小鼠模型中发现的机制对于人类糖尿病患者是否同样重要的转化研究将至关重要。
Adults with diabetes are much more likely to suffer from cardiovascular disease than those without diabetes. Genetically engineered mouse models have started to provide important insight into the mechanisms whereby diabetes promotes atherosclerosis. Such models have demonstrated that diabetes promotes formation of atherosclerotic lesions, progression of lesions into advanced hemorrhaged lesions, and that it prevents lesion regression. The pro-atherosclerotic effects of diabetes are driven in part by the altered function of myeloid cells. The protein S100A9 and the receptor for advanced glycation end-products are important mediators of the effect of diabetes on myelopoiesis. Furthermore, myeloid cell expression of the enzyme acyl-CoA synthetase 1 (ACSL1), which converts long-chain fatty acids into their acyl-CoA derivatives, has emerged as causal to diabetes-induced lesion initiation. The protective effects of S100A9-deficiency and myeloid ACSL1-deficiency in diabetic mice, but not in non-diabetic mice, indicate that myeloid cells are activated by diabetes through mechanisms that play minor roles in the absence of diabetes. The roles reactive oxygen species and insulin resistance in diabetes-accelerated atherosclerosis are also discussed, primarily in relation to endothelial cells. Translational studies addressing whether the mechanisms identified in mouse models are equally important in humans with diabetes will be paramount.