Metformin Improves the Function of Abdominal Aortic Aneurysm Patient-Derived Aortic Smooth Muscle Cells

Tara A R van Merrienboer; Karlijn B Rombouts; Natalija Bogunovic; Arnout Mieremet; Jorn P Meekel; Ron Balm; Vivian de Waard; Kak K Yeung

doi:10.1016/j.ejvs.2024.09.022

Metformin Improves the Function of Abdominal Aortic Aneurysm Patient-Derived Aortic Smooth Muscle Cells

Eur J Vasc Endovasc Surg. 2024 Sep 24:S1078-5884(24)00814-1. doi: 10.1016/j.ejvs.2024.09.022. Online ahead of print.

Authors

Tara A R van Merrienboer¹, Karlijn B Rombouts², Natalija Bogunovic³, Arnout Mieremet⁴, Jorn P Meekel³, Ron Balm³, Vivian de Waard⁴, Kak K Yeung²

Affiliations

¹ 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. Electronic address: t.vanmerrienboer@amsterdamumc.nl.
² 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.
³ Amsterdam UMC location University of Amsterdam, Surgery, Amsterdam, the Netherlands.
⁴ Amsterdam UMC location University of Amsterdam, Medical Biochemistry, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Atherosclerosis & Ischaemic Syndromes, Amsterdam, the Netherlands.

PMID: 39321955
DOI: 10.1016/j.ejvs.2024.09.022

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: This study found that metformin increases contractility and metabolic activity, and reduces proliferation, migration, and inflammation in aortic SMCs in vitro.

Keywords: AAA; Abdominal aortic aneurysm; Metformin; Myocyte; Smooth muscle.