O-206 - METFORMIN AS MEDICAL THERAPY FOR ABDOMINAL AORTIC ANEURYSMS: HOW DOES IT WORK?

TOPIC:
Medical therapies (antithrombotic, anti-hypertensive, diabetes mellitus etc.)
AUTHORS:
Van Merrienboer T. (Amsterdam UMC ~ Amsterdam ~ Netherlands) , Rombouts K. (Amsterdam UMC ~ Amsterdam ~ Netherlands) , Meekel J. (Amsterdam UMC ~ Amsterdam ~ Netherlands) , Bogunovic N. (Amsterdam UMC ~ Amsterdam ~ Netherlands) , Yeung K.K. (Amsterdam UMC ~ Amsterdam ~ Netherlands)
Introduction:
A negative relationship exists between diabetes mellitus (DM) and abdominal aortic aneurysms (AAA), which is possibly caused by use of metformin. The aim of this study is to examine the difference in smooth muscle cell (SMC) contractile phenotype, proliferation capacity and metabolic activity of non-pathologic aortic controls, non-diabetic AAA patients and diabetic AAA patients. In addition, we investigate the therapeutic effect of metformin on these SMC functions.
Methods:
Aortic biopsies were perioperative obtained from AAA patients (n = 20) and controls (n = 15). SMCs of non-pathologic aortic controls, non-diabetic AAA patients and diabetic AAA patients were treated with 10 mM metformin and a selection left untreated as negative control. After five days metabolic activity measurement was done with the WST-1 assay and proliferation was evaluated by counting the amount of produced protein. The contractility was tested using Electric Cell-substrate Impedance Sensing (ECIS) upon ionomycin stimulation after 60 hours of metformin treatment.
Results:
No significant difference was seen in baseline contractility, proliferation and metabolic activity in SMCs of the three study groups. However, metformin had a significant effect on the tested SMC functions. Metformin elevated the contraction in SMC of controls (n=11), non-diabetic AAA patients (n=11) and diabetic AAA patients (n=4) (p<0.068). The contraction increased significant (p=0.004) after treatment with metformin in SMCs of non-diabetic AAA patients [Figure 1]. Furthermore, a significant increase of metabolic activity (p<0.028) and a significant decrease of proliferation capacity (p<0.018) was found in SMCs of controls (n=15), non-diabetic AAA patients (n=13) and diabetic AAA patients (n=7) after treatment with metformin.
Conclusion:
Metformin treatment has a direct effect on SMC function of AAA patients by decreasing proliferation capacity and increasing contractility and metabolic activity. We will expand the sample size and complement the research groups. Activation of AMPK signaling pathway is proposed to be responsible for multiple positive effects of metformin. We will perform a small interfering RNA knockdown of the AMPKα pathway to explicate possible other involved pathways and we hope to identify more therapeutic targets of Metformin in AAA with whole genome sequencing.
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