脂联素调控线粒体自噬及ROS生成进而保护高血压心脏纤维化的机制研究

In recent years the incidence of hypertension in China increased rapidly. The hypertension-induced cardiovascular damage has been a serious threat to the national health. One of the important pathologic characteristics of hypertensive remodeling is the cardiac fibrosis, which is the main factor leading to heart failure. In cardiac fibrosis there are infiltration and activation of many inflammatory cells, and the key points are oxidative stress and macrophage activation. Adiponectin, an important active factor for cardiovascular protection, could inhibit macrophage- mediated inflammation. Some studies suggested adiponectin protected target-organ damage caused by hypertension, and however the mechanism that adiponectin regulates inflammation and oxidative stress remains unclear. Our previous studies found that adiponectin-deficiency suppressed autophagy activity and promoted cardiac inflammation and fibrosis in hypertensive mice. Therefore, we proposed the hypothesis: adiponectin could protect against cardiac fibrosis-caused by hypertension through regulating macrophage mitophagy and oxidative stress. In the research we will apply gene knockout mice, respective deficiency of adiponectin or autophagy-related gene 5 (Atg5), to make hypertensive mouse model via angiotensin II infusion, and take mouse primary cells for vitro experiments and finally detect via pathologic and molecular biology techniques. We will determine the molecular mechanism that during early stage of hypertensive cardiac injury adiponectin could reduce ROS production through activating macrophage mitophagy and inhibit inflammation and fibrosis. The study findings will help to provide new theory and latent treatment target for hypertensive cardiac fibrosis.

近年我国高血压发病率逐年上升，高血压导致的心血管损伤严重威胁国民健康。心脏纤维化是高血压病理重塑重要特征，是导致心力衰竭主要因素，其中存在多种炎症细胞浸润活化，其核心环节之一是氧化应激及巨噬细胞激活。脂联素是重要心血管保护因子，可抑制巨噬细胞介导的炎症反应。研究认为脂联素保护高血压靶器官损伤，但其调节炎症反应及氧化应激的具体机制仍不明确。我们前期研究发现脂联素基因缺陷抑制细胞自噬活性，促进高血压小鼠心脏炎症反应及纤维化。因此我们提出假设：脂联素通过调节巨噬细胞自噬及氧化应激而保护高血压心脏纤维化。本课题拟应用脂联素及自噬相关基因Atg5敲除小鼠，采用血管紧张素II灌注制备高血压模型，结合原代细胞实验，运用病理及分子生物学技术，明确高血压心脏损伤早期阶段，脂联素激活巨噬细胞线粒体自噬，减少ROS生成，抑制炎症反应及纤维化的分子机制，从而为高血压心脏纤维化的防治提供新的理论依据及潜在治疗靶点。

巨噬细胞活化及炎症反应在高血压心脏重塑过程中发挥了极其重要的作用。本研究使用基因敲除小鼠，采用血管紧张素II灌注制备高血压模型，运用病理学、分子生物学、流式细胞等实验技术检测炎症细胞浸润、胶原沉积、自噬小体形成以氧自由基释放，结果表明脂联素通过激活AMPK-Atg5通路，调控巨噬细胞浸润及自噬活性，从而抑制ROS生成和炎症损伤而发挥心脏保护效应，从而为高血压心脏纤维化的防治提供新的理论依据及潜在治疗靶点。