Adropin抗动脉粥样硬化作用及lncRNA HDAC11-AS1调控机制

Adropin is an endogenesis active peptide to inhibit the development of atherosclerosis(As), but the regulation mechanisms are still not clear..Preliminary experiments had confirmed that HDAC11 could catalyze adropin histone deacetylation and decrease adropin expression. While the treatment with lncRNA HDAC11-AS1 had opposite results. We hypothesize that HDAC11 may induce adropin histone deacetylation, lncRNA HDAC11-AS1 may target to silence HDAC11 expression to reduce adropin histone deacetylation level which can boost adropin expression to promote LPL expression and prevent As. To test this hypothesis, we first silence or over-express HDAC11 to measure the deacetylation levels of adropin histones, the level of adropin and LPL. We then silence or over-express lncRNA HDAC11-AS1 to detect the expression level and activity of HDAC11, deacetylation levels of adropin histones, the expression level of adropin and LPL. Finally, we explore the effects of overexpression or silence of both HDAC11 and lncRNA HDAC11-AS1 on aortic As plaque area, adropin histone deacetylation levels and blood lipid levels in apoE knockout mice. The project will unveil the mechanisms of adropin histone deacetylation regulation and provide new targets andtheoretical foundations for As prophylaxis and treatment.

Adropin（Adr）是一种内源性活性肽，具有抗动脉粥样硬化(As)作用，但其调控机制未明。预实验发现HDAC11促进Adr组蛋白去乙酰化，下调其表达；lncRNA HDAC11-AS1能逆转该作用。据此我们提出科学假说：“lncRNA HDAC11-AS1靶向沉默HDAC11，抑制Adr组蛋白去乙酰化，上调Adr和脂蛋白酯酶（LPL）表达，降低TG水平，抗As”。项目拟过表达或沉默HDAC11，检测Adr组蛋白去乙酰化水平、Adr和LPL表达；过表达或沉默lncRNA HDAC11-AS1检测Adr组蛋白去乙酰化水平、HDAC11、Adr和LPL表达；过表达或沉默HDAC11、lncRNA HDAC11-AS1，观察apoE敲除小鼠主动脉Adr组蛋白去乙酰化水平、Adr及LPL表达、血脂水平及As斑块面积。该项目有望揭示Adr组蛋白去乙酰化调控机制，为As防治提供新靶点和L理论依据。

动脉粥样硬化(As)是心脑血管疾病共同的病理基础，严重危害人类健康。高甘油三酯血症是As相关心脑血管疾病发生的独立危险因素，而脂蛋白酯酶(LPL)是水解甘油三酯的关键限速酶。分泌性蛋白adropin可调节脂质代谢，同时，有研究证实adropin可上调罗非鱼肝细胞中LPL的表达，但其具体机制未明。HDAC11是催化基因组蛋白去乙酰化的关键酶，生物信息学分析发现，lncRNA¬ HDAC11-AS1和HDAC11定位于同一染色体上（3q25），且转录方向相反，提示lncRNA¬ HDAC11-AS1是HDAC11的天然反义转录物（NATs）。本项目分别用HDAC11、lncRNA HDAC11-AS1及其各自的siRNA转染HA-VSMCs和高脂喂养的apoE-/-小鼠，检测了HDAC11、adropin和LPL的表达、adropin组蛋白去乙酰化水平、小鼠各项血脂水平、主动脉As斑块面积。探讨了lncRNA HDAC11-AS1通过靶向沉默HDAC11影响adropin组蛋白去乙酰化的机制，同时探究了adropin组蛋白去乙酰化对apoE-/-小鼠As的影响及lncRNA HDAC11-AS1调控途径。研究取得以下重要发现：（1）HDAC11增加HA-VSMCs内adropin组蛋白去乙酰化水平，进而抑制adropin表达；（2）lncRNA¬ HDAC11-AS1通过HDAC11抑制adropin组蛋白去乙酰化水平，使adropin表达增加；（3）adropin通过AMPK通路促进LPL表达；（4）lncRNA HDAC11-AS1抑制apoE-/-小鼠As斑块内的脂质蓄积、血浆脂质水平，延缓As病变的发生发展。本项目研究结果揭示了adropin组蛋白去乙酰化调控机制及lncRNA HDAC11-AS1的抗As作用，为As防治提供了新靶点和理论依据。