Aminoguanidine reduces diabetes‑associated cardiac fibrosis

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.

AGEs–RAGE axis mediates myocardial fibrosis via activation of cardiac fibroblasts induced by autophagy in heart failure

“…Many studies have shown that AGEs mediate pathological conditions such as diabetes, cardiac dysfunction, renal failure and Alzheimer's disease (Deluyker et al., 2017). Moreover, inhibition of AGEs can reduce oxidative stress‐associated cardiac fibrosis (Magdaleno et al., 2019). Surprisingly, some studies indicate that plasma AGEs levels are associated with the development of heart failure and even suggest targeting AGEs as a potential therapy in heart failure (Campbell et al., 2012; Hegab, 2012).…”

Advanced Glycation End Product Blocker Drugs Have a Great Potential to Prevent Diabetic Cardiomyopathy in an Animal Model of Diabetes Mellitus Type-2

“…The most similar study to ours is an article by Magdaleno et al They used 20 mg/kg AG in diabetic rats to assess the effects of this drug on cardiac fibrosis. They showed that AG inhibits cardiac fibrosis by ERK1/2 and SMAD2/3 pathways (supplementary data figure- 10 and Figure 11 ) [ 15 ]. Our study's privilege to their study is that we practically showed the positive effects of AG on cardiac function by TTE.…”

“…Both groups were divided into four equal subgroups. All rats were matched in weight and age [ 15 ]. Healthy subgroups were healthy rats with high fat-high carbohydrate (HFHC) diet (CS group), healthy rats were treated with oral 50 mg/kg of AG plus HFHC diet (S50 group), healthy rats were treated with oral 100 mg/kg of AG plus HFHC diet (S100 group), and healthy rats were treated with oral 200 mg/kg of AG plus HFHC diet (S200 group).…”

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“…Advanced glycation end products (AGEs) and ROS produced by enhanced glucose metabolism cumulate in organs and tissues, causing typical micro and macrovascular changes in diabetic patients directing to an enlarged vulnerability to a Rhizopus infection. 100 , 101 Due to inadequacy of the cofactor NADPH, downregulation of the major antioxidant system of glutathione (GSH/GSSG), which is the prime requirement for the reconstruction of reduced glutathione, ultimately reduces the ability of the patient to control the oxidative stress. The polyol route for glucose metabolism consumes NADPH quickly, resulting in a deficit of NADPH.…”