van Merrienboer Tara A R, Rombouts Karlijn B, Bogunovic Natalija, Mieremet Arnout, Meekel Jorn P, Balm Ron, de Waard Vivian, Yeung Kak K
Amsterdam UMC location University of Amsterdam, Surgery, Amsterdam, the Netherlands; Amsterdam UMC location Vrije Universiteit Amsterdam, Physiology, Amsterdam, the Netherlands; Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Atherosclerosis & Ischaemic Syndromes, Amsterdam, the Netherlands.
Amsterdam UMC location University of Amsterdam, Surgery, Amsterdam, the Netherlands; Amsterdam UMC location Vrije Universiteit Amsterdam, Physiology, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Atherosclerosis & Ischaemic Syndromes, Amsterdam, the Netherlands.
Eur J Vasc Endovasc Surg. 2025 Mar;69(3):485-495. doi: 10.1016/j.ejvs.2024.09.022. Epub 2024 Sep 24.
Type 2 diabetes mellitus (T2DM) is a cardiovascular risk factor. Paradoxically, a decreased risk of abdominal aortic aneurysm (AAA) presence and growth rate is described among patients with T2DM, associated with metformin use. This study aimed to investigate the effect of metformin on AAA patient-derived aortic smooth muscle cell (SMC) function.
Aortic biopsies were obtained from patients with AAA (n = 21) and controls (n = 17) during surgery. The SMCs of non-pathological aortic controls, non-diabetic patients with AAA, and diabetic patients with AAA were cultured from explants and treated with or without metformin. The SMC contractility was measured upon ionomycin stimulation, as well as metabolic activity, proliferation, and migration. mRNA and protein expression of markers for contraction, metabolic activity, proliferation, and inflammation were measured.
mRNA expression of KLF4 and GYS1, genes involved in metabolic activity, differed between SMCs from non-diabetic and diabetic patients with AAA before metformin stimulation (p < .041). However, the effect of metformin on the various SMC functions was similar between non-diabetic and diabetic patients with AAA. Upon stimulation, metformin increased the contractility of AAA patient SMCs (p = .001). mRNA expression of smoothelin, a marker for the contractile phenotype, increased in SMCs of patients with AAA after treatment with metformin (p = .006). An increase in metabolic activity (p < .001) and a decrease in proliferation (p < .001) and migration were found in the SMCs of controls and patients with AAA with metformin. Increased mRNA expression of PPARγ, a nuclear receptor involved in mitochondrial biogenesis (p < .009), and a decrease in gene expression of Ki-67, a marker for proliferation (p < .005), were observed. Gene expression of inflammation markers MCP-1 and IL-6, and protein expression of NF-κB p65 decreased after treatment with metformin in patients with AAA.
This study found that metformin increases contractility and metabolic activity, and reduces proliferation, migration, and inflammation in aortic SMCs in vitro.
2型糖尿病（T2DM）是一种心血管危险因素。矛盾的是，在使用二甲双胍的T2DM患者中，腹主动脉瘤（AAA）的发生风险和生长速率有所降低。本研究旨在探讨二甲双胍对源自AAA患者的主动脉平滑肌细胞（SMC）功能的影响。
在手术过程中从AAA患者（n = 21）和对照组（n = 17）获取主动脉活检组织。从外植体培养非病理性主动脉对照组、非糖尿病AAA患者和糖尿病AAA患者的SMC，并给予或不给予二甲双胍处理。在离子霉素刺激后测量SMC的收缩性，以及代谢活性、增殖和迁移情况。检测收缩、代谢活性、增殖和炎症相关标志物的mRNA和蛋白表达。
在二甲双胍刺激前，参与代谢活性的基因KLF4和GYS1的mRNA表达在非糖尿病和糖尿病AAA患者的SMC之间存在差异（p <.041）。然而，二甲双胍对非糖尿病和糖尿病AAA患者各种SMC功能的影响相似。刺激后，二甲双胍增加了AAA患者SMC的收缩性（p =.001）。在用二甲双胍治疗后，AAA患者SMC中收缩表型标志物平滑肌肌动蛋白的mRNA表达增加（p =.006）。在对照组和AAA患者的SMC中，二甲双胍使代谢活性增加（p <.001），增殖（p <.001）和迁移减少。观察到参与线粒体生物发生的核受体PPARγ的mRNA表达增加（p <.009），以及增殖标志物Ki-67的基因表达减少（p <.005）。在AAA患者中，用二甲双胍治疗后炎症标志物MCP-1和IL-6的基因表达以及NF-κB p65的蛋白表达降低。
本研究发现二甲双胍可增加体外主动脉SMC的收缩性和代谢活性，并减少其增殖、迁移和炎症反应。
