高糖环境下lncRNA-ES3调控糖尿病性血管衰老/钙化中的作用及机制

血管衰老/钙化是糖尿病大血管病变的重要特征，可导致严重心血管事件，防治困难。高糖可刺激血管平滑肌细胞（VSMCs)衰老/钙化而导致糖尿病性血管衰老/钙化。长链非编码RNA（lncRNA）与糖尿病血管病变密切相关，是潜在干预靶点，但其与高糖刺激VSMCs衰老/钙化相关研究极少。我们前期首次报道lncRNA-ES3参与高糖刺激的VSMCs衰老/钙化，但机制未明。预实验发现：高糖刺激VSMCs衰老/钙化过程中lncRNA-ES3上调，其上游Bhlhe40及下游miR-95-5p下调。故提出假说：高糖环境下Bhlhe40失调引起lncRNA-ES3表达增加，从而抑制miR-95-5p表达，后者通过调控HDAC2/8促进VSMCs衰老/钙化，是糖尿病性血管衰老/钙化新发病机制之一。本项目通过细胞、动物、临床三个层面验证假说，将揭示糖尿病性血管衰老/钙化新的调控机制，为防治该病提供新思路及理论依据。

Vascular aging/calcification is a crucial feature of diabetic macro vasculopathy, resulting in serious cardiovascular events and tough prophylaxis and treatment. The senescence/calcification of vascular smooth muscle cells (VSMCs) induced by high glucose can cause diabetic vascular aging/calcification. It is known that long noncoding RNA (lncRNA) was closely related to diabetic angiopathy as well as a potential therapeutic target, while there were few studies reported about its roles in high-glucose-induced senescence/calcification of VSMCs. Our preliminary study demonstrated for the first time that lncRNA-ES3 was involved in regulating high-glucose-induced senescence/calcification of VSMCs, but the specific mechanisms were not fully elucidated. Our previous study found that the expression of lncRNA-ES3 was up-regulated, accompanying with the down-regulation of upstream Bhlhe40 and downstream miR-95-5p in VSMCs under hyperglycemia. Herein, we hypothesize that Bhlhe40 is deregulated in VSMCs under hyperglycemia, leading to the up-regulation of lncRNA-ES3, which in turn inhibits the expression of miR-95-5p. And then the decreased miR-95-5p influences the senescence/calcification of VSMCs through regulating HDAC2/8. This is a novel pathogenesis of diabetic vascular aging/calcification. We will test this hypothesis both in vitro and in vivo, from both animal models and clinical patients. The result of this study will reveal a new regulatory mechanism of diabetic vascular aging/calcification and provide a new train of thought and theoretical basis for the prevention and treatment of diabetic vascular aging/calcification.