Atherosclerotic plaque rupture followed by luminal thrombosis is recognized as the main cause of acute cardiovascular events, especially in patients with diabetes. Although previous studies identified stimulation of macrophages polarization with advanced glycation end products (AGEs) results in the rapid progression of atherosclerosis, the underlying mechanisms are not understood fully. The purpose of this study was to investigate the effect of hypoxia-inducible factor-1α (HIF-1α) and pyruvate dehydrogenase kinase 4 (PDK4), critical proteins for regulating glucose metabolism, on macrophages polarization in diabetic atherosclerosis, and relevant mechanisms involved. We found that there is an increased number of M1 macrophages in carotid atherosclerotic tissues of diabetic mice and in AGE-bovine serum albumin (BSA)-treated RAW264.7 cells. Furthermore, we observed that HIF-1α was upregulated in AGE-BSA-induced M1 polarization and that the HIF-1α knockdown reduced macrophage polarization to M1 phenotype caused by AGE-BSA via regulation of PDK4. Thus, our study identified the critical role of HIF-1α/PDK4 axis in AGE-BSA-induced M1 polarization, which reflected the potential association between energy metabolism and inflammation in macrophages.

动脉粥样硬化斑块破裂，然后腔内血栓形成被认为是急性心血管事件的主要原因，尤其是在糖尿病患者中。尽管以前的研究发现先进的糖基化终末产物（AGEs）刺激巨噬细胞极化会导致动脉粥样硬化的快速发展，但其潜在机制仍未完全了解。这项研究的目的是研究缺氧诱导因子-1α（HIF-1α）和丙酮酸脱氢酶激酶4（PDK4），调节葡萄糖代谢的关键蛋白对糖尿病动脉粥样硬化中巨噬细胞极化的影响及其相关机制。我们发现糖尿病小鼠的颈动脉粥样硬化组织和AGE-牛血清白蛋白（BSA）处理的RAW264.7细胞中M1巨噬细胞的数量增加。此外，我们观察到HIF-1α在AGE-BSA诱导的M1极化中被上调，并且HIF-1α的敲低通过调节PDK4将AGE-BSA引起的巨噬细胞极化降低为M1表型。因此，我们的研究确定了HIF-1α/ PDK4轴在AGE-BSA诱导的M1极化中的关键作用，这反映了能量代谢与巨噬细胞炎症之间的潜在关联。