Effects of glucose and insulin resistance on gene expression profiling in the isolated working rat heart

The changes were highly similar to gene alterations occurring in the right atrium and left ventricle of open heart surgery patients, and included the up-regulation of the three master regulators of metabolic reprogramming MYC, NR4A1 and NR4A2. Targeted pathway analysis revealed an up-regulation of metabolic processes associated with the proliferation and activation of tissue-resident macrophages and fibroblasts. Although the remodeling occurred independently from glucose, glucose further increased the expression of a subset of genes associated with polarization of tissue reparative M2 macrophages. However, glucose failed to enhance the expression of M2-related markers in the isolated heart from rats rendered insulin resistant by high-sucrose feeding. These results expose the cellular components of the heart as a significant source of proinflammatory mediators released in response to stress associated with cardiac surgery with CPB, and suggest a major role for glucose as a signal in the determination of resident cardiac macrophage polarization.该研究观测到的基因表达变化与心脏直视手术患者右心房（right atrium）和左心室（left ventricle）内发生的基因改变高度相似，且包含代谢重编程（metabolic reprogramming）三大主调控因子MYC、NR4A1及NR4A2的上调。靶向通路分析（targeted pathway analysis）显示，与组织驻留巨噬细胞（tissue-resident macrophages）和成纤维细胞（fibroblasts）的增殖及活化相关的代谢过程出现上调。尽管该心脏重塑过程不依赖葡萄糖，但葡萄糖可进一步上调与组织修复型M2巨噬细胞（tissue reparative M2 macrophages）极化相关的部分基因的表达。然而，在经高蔗糖喂养诱导产生胰岛素抵抗（insulin resistance）的大鼠离体心脏中，葡萄糖无法提升M2相关标志物的表达水平。上述结果揭示，心脏细胞组分是体外循环（cardiopulmonary bypass, CPB）辅助心脏手术相关应激所释放的促炎介质（proinflammatory mediators）的重要来源，同时提示葡萄糖作为信号分子，在调控心脏驻留巨噬细胞极化方向中发挥核心作用。