HDAC2调控Inpp5f对糖尿病心肌缺血再灌注损伤的作用及分子机制

Diabetes increases heart susceptibility to ischemia/reperfusion (IR) injury, which has been correlated with high occurrence of complication and mortality in diabetic patients suffering from acute coronary syndrome. It has been suggested that impaired PI3K/Akt signal pathway is responsible for the increased susceptibility to myocardial injury during IR. Phosphatase, inositol polyphosphate-5- phosphatase F (Inpp5f) has recently been implicated in the negative regulation of PI-3K/Akt pathway. Our recent research shows that p-Akt was remarkably reduced in diabetic heart, which was accompanied with increased expression of Inpp5f. These indicate that Inpp5f plays an important role during diabetic myocardial IR injury. Histone deacetylase 2 (HDAC2), a well-known molecule in regulation of transcription, has been reported negatively regulates gene expression of Inpp5f. With transgenic overexpression and gene inactivation in our in-vivo and in-vitro model of diabetes, we will examined the contribution of HDAC2 and Inpp5f towards myocardial ischemia reperfusion injury, and more importantly, try to address whether HDAC2- Inpp5f can reduce myocardial injury through activation of PI-3K/Akt pathway. This study will provide a novel strategy for protecting diabetic hearts from IR injury.

糖尿病增加心肌缺血再灌注损伤的易损性，进而增加患者围术期并发症和死亡率。PI-3K/Akt信号通路激活受损导致糖尿病心肌缺血再灌注损伤易损性增加，磷酸酶Inpp5f是新近发现的PI-3K/Akt信号通路的重要负向调控分子，抑制Inpp5f可显著促进Akt的激活。我们研究显示，糖尿病心肌Inpp5f明显增加、Akt的激活减少，与糖尿病心肌易损性增加密切相关。而HDAC2对Inpp5f具有重要的调控作用，但能否通过调控Inpp5f减轻糖尿病心肌缺血再灌注损伤亟待阐明。本课题拟通过建立糖尿病心肌缺血再灌注损伤模型，以大鼠在体及培养的心肌细胞为研究对象，利用基因转染和沉默技术研究HDAC2对Inpp5f的调控作用及机制，阐明HDAC2介导Inpp5f，促进PI-3K/Akt信号通路及其下游作用分子的激活，减轻糖尿病心肌缺血再灌注损伤，为更有效防治糖尿病心肌缺血再灌注损伤提供理论依据。

糖尿病增加心肌缺血再灌注损伤的易损性，进而增加患者围术期并发症和死亡率。这可能与PI-3K/Akt通路失活有关，但详细机制未明。磷酸酶Inpp5f是新近发现的PI-3K/Akt信号通路的重要负向调控分子，抑制Inpp5f可显著促进Akt的激活。我们研究表明：（1）在体和离体实验中，糖尿病心肌HDAC2活性降低、Inpp5f明显增加、Akt的激活减少，这与糖尿病心肌易损性增加密切相关。（2）HDAC2特异性抑制剂加重了糖尿病心肌缺血再灌注损伤，这说明HDAC2是心肌易损性增加的关键。（3）在高糖缺氧复氧损伤模型中，上调心肌细胞HDAC2的表达，inpp5f的表达下降,Akt磷酸化程度升高，细胞损伤减轻。（4）沉默HDAC2基因，inpp5f表达上调，Akt磷酸化程度下降，细胞损伤加重，这表明HDAC2对Inpp5f具有负性调控作用。（5）下调inpp5f的表达，p-Akt的表达升高，这表明在该损伤模型中，inpp5f是PI-3K/Akt信号通路的重要调节因子。（6）HDAC2/inpp5f/Akt是糖尿病心肌缺血再灌注损伤的重要调节通路。基于我们的上述研究，以期待为糖尿病心脏缺血/再灌注损伤的防治提供有效的治疗靶点。