Aminoguanidine reduces diabetes‑associated cardiac fibrosis

Magdaleno,Fernando; Blajszczak,Chuck   Christopher; Charles‑Niño,Claudia  Lisette; Guadrón‑Llanos,Alma   Marlene; Vázquez‑Álvarez,Alan   Omar; Miranda‑Díaz,Alejandra   Guillermina; Nieto,Natalia; Islas‑Carbajal,María  Cristina; Rincón‑Sánchez,Ana   Rosa

doi:10.3892/etm.2019.7921

Aminoguanidine reduces diabetes‑associated cardiac fibrosis

Authors:
- Fernando Magdaleno
- Chuck Christopher Blajszczak
- Claudia Lisette Charles‑Niño
- Alma Marlene Guadrón‑Llanos
- Alan Omar Vázquez‑Álvarez
- Alejandra Guillermina Miranda‑Díaz
- Natalia Nieto
- María Cristina Islas‑Carbajal
- Ana Rosa Rincón‑Sánchez
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Affiliations: Department of Physiology, University Center of Health Sciences, Guadalajara University, Guadalajara, Jalisco 44340, Mexico, Department of Pathology, College of Medicine, University of Illinois at Chicago, IL 60612, USA, Institute of Experimental and Clinical Therapeutics, Department of Physiology, University Center of Health Sciences, Guadalajara University, Guadalajara, Jalisco 44340, Mexico, Institute of Molecular Biology and Gene Therapy, Department of Molecular Biology and Genomics, University Center of Health Sciences, Guadalajara University, Guadalajara, Jalisco 44340, Mexico
Published online on: August 20, 2019 https://doi.org/10.3892/etm.2019.7921
Pages: 3125-3138

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Abstract

Aminoguanidine (AG) inhibits advanced glycation end products (AGEs) and advanced oxidation protein products (AOPP) accumulated as a result of excessive oxidative stress in diabetes. However, the molecular mechanism by which AG reduces AGE‑associated damage in diabetes is not well understood. Thus, we investigated whether AG supplementation mitigates oxidative‑associated cardiac fibrosis in rats with type 2 diabetes mellitus (T2DM). Forty‑five male Wistar rats were divided into three groups: Control, T2DM and T2DM+AG. Rats were fed with a high‑fat, high‑carbohydrate diet (HFCD) for 2 weeks and rendered diabetic using low‑dose streptozotocin (STZ) (20 mg/kg), and one group was treated with AG (20 mg/kg) up to 25 weeks. In vitro experiments were performed in primary rat myofibroblasts to confirm the antioxidant and antifibrotic effects of AG and to determine if blocking the receptor for AGEs (RAGE) prevents the fibrogenic response in myofibroblasts. Diabetic rats exhibited an increase in cardiac fibrosis resulting from HFCD and STZ injections. By contrast, AG treatment significantly reduced cardiac fibrosis, α‑smooth muscle actin (αSMA) and oxidative‑associated Nox4 and Nos2 mRNA expression. In vitro challenge of myofibroblasts with AG under T2DM conditions reduced intra‑ and extracellular collagen type I expression and Pdgfb, Tgfβ1 and Col1a1 mRNAs, albeit with similar expression of Tnfα and Il6 mRNAs. This was accompanied by reduced phosphorylation of ERK1/2 and SMAD2/3 but not of AKT1/2/3 and STAT pathways. RAGE blockade further attenuated collagen type I expression in AG‑treated myofibroblasts. Thus, AG reduces oxidative stress‑associated cardiac fibrosis by reducing pERK1/2, pSMAD2/3 and collagen type I expression via AGE/RAGE signaling in T2DM.

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