Department of Endocrinology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University & The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China.
Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.
Biochem Biophys Res Commun. 2021 Jun 11;557:334-341. doi: 10.1016/j.bbrc.2021.04.029. Epub 2021 Apr 26.
Atherosclerosis is a chronic lipid disfunction and inflammatory disease, which is characterized with enriched foam cells and necrotic core underneath the vascular endothelium. Therefore, the inhibition of foam cell formation is a critical step for atherosclerosis treatment. Metformin, a first-line treatment for Type 2 diabetes, is reported to be beneficial to cardiovascular disease. However, the mechanism underlying the antiatherogenic effect of metformin remains unclear. Macrophage autophagy is reported to be a highly anti-atherogenic process that promotes the catabolism of cytosolic lipid to maintain cellular lipid homeostasis. Notably, dysfunctional autophagy in macrophages plays a detrimental role during atherogenesis. Krueppel-like factor 2 (KLF2) is an important transcription factor that functions as a key regulator of the autophagy-lysosome pathway. While the role of KLF2 in foam cell formation during the atherogenesis remains elusive. In this study, we first investigated whether metformin could protect against atherogenesis via enhancing autophagy in high fat diet (HFD)-induced apoE mice. Subsequently, we further determined the molecular mechanism that whether metformin could inhibit foam cell formation by activating KLF2-mediated autophagy. We show that metformin protected against HFD-induced atherosclerosis and enhanced plaque stability in apoE mice. Metformin inhibits foam cell formation and cellular apoptosis partially through enhancing autophagy. Mechanistically, metformin promotes autophagy via modulating KLF2 expression. Taken together, our study demonstrates a novel antiatherogenic mechanism of metformin by upregulating KLF2-mediated autophagy.
动脉粥样硬化是一种慢性脂质功能障碍和炎症性疾病，其特征是血管内皮下富含泡沫细胞和坏死核心。因此，抑制泡沫细胞的形成是动脉粥样硬化治疗的关键步骤。二甲双胍是治疗 2 型糖尿病的一线药物，据报道对心血管疾病有益。然而，二甲双胍抗动脉粥样硬化作用的机制尚不清楚。巨噬细胞自噬被报道是一种高度抗动脉粥样硬化的过程，它促进细胞溶质脂质的分解代谢，以维持细胞脂质的平衡。值得注意的是，巨噬细胞中功能失调的自噬在动脉粥样发生过程中起着有害的作用。Krüppel 样因子 2（KLF2）是一种重要的转录因子，作为自噬溶酶体途径的关键调节因子发挥作用。而 KLF2 在动脉粥样硬化形成过程中对泡沫细胞形成的作用仍不清楚。在本研究中，我们首先研究了二甲双胍是否可以通过增强高脂肪饮食（HFD）诱导的 apoE 小鼠中的自噬来预防动脉粥样硬化。随后，我们进一步确定了二甲双胍是否可以通过激活 KLF2 介导的自噬来抑制泡沫细胞形成的分子机制。我们发现二甲双胍可以预防 HFD 诱导的 apoE 小鼠动脉粥样硬化和增强斑块稳定性。二甲双胍通过增强自噬部分抑制泡沫细胞形成和细胞凋亡。在机制上，二甲双胍通过调节 KLF2 的表达来促进自噬。总之，我们的研究表明，二甲双胍通过上调 KLF2 介导的自噬来发挥其抗动脉粥样硬化作用的新机制。
