Oral Treatment With Metformin Prevents Early Signs of AGE/RAGE-Induced Aortic Arteriosclerosis in Rats With Metabolic Syndrome
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Abstract
Introduction: Metabolic syndrome (MS) is associated with increased carbonyl stress, accumulation of advanced glycation end products (AGE), and induction of arterial calcifications (AC) through the osteoblastic transdifferentiation of vascular smooth muscle cells (VSMC). Metformin (MET) inhibits this transdifferentiation in vitro. We evaluated whether oral MET can prevent AC in an experimental model of MS.
Materials and Methods: young adult male Wistar rats were divided into two groups: one received water as the drinking source (C) and the other a 20% fructose solution (F). After two weeks, and for an additional four weeks, each group was subdivided, and MET (100 mg/kg/day) was added to the drinking water of one half (thus, M and FM). Metabolic and body parameters were measured. The aorta was dissected for histomorphometric and immunohistochemical analyses. Aortic VSMC were isolated to assess alkaline phosphatase (ALP) activity, collagen production, extracellular matrix mineralization, and gene expression of Runx2 and the receptor for AGE (RAGE).
Results: group F developed features consistent with MS, including increased adiposity, non-fasting hyperglycemia, dyslipidemia, and elevated serum fructosamine. Aortas from F animals showed a reduced elastic-to-muscular ratio, increased collagen content, AGE accumulation, and RAGE overexpression. VSMC from F rats displayed higher ALP activity, increased collagen production and mineralization, and elevated expression of Runx2 and RAGE. Cotreatment with MET prevented all these MS-induced alterations. In vitro, MET blocked AGE-induced RAGE upregulation by VSMC, an effect abolished by an AMP-activated protein kinase (AMPK) inhibitor.
Conclusion: these findings indicate that oral MET treatment attenuates extracellular glycation, AGE/RAGE activation, and vascular remodeling associated with experimental MS.
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