Multifaceted elucidation of aminoguanidine in protecting against diabetes-induced vascular endothelial injury

Abstract

Chronic hyperglycemia-driven protein glycation in diabetes is a key pathogenic factor in vascular endothelial injury. This study demonstrates the multifaceted protective profile of aminoguanidine (AMG) against diabetes-induced vascular injury. As a carbonyl scavenger, AMG effectively traps methylglyoxal (MGO), inhibiting advanced glycation end products (AGEs) formation while preserving endothelial glycocalyx integrity and permeability. Mechanistically, AMG suppresses NF-κB-mediated inflammation, upregulates the eNOS/NO pathway, and restores CD31 expression, collectively mitigating oxidative stress, apoptosis and impaired proliferation in human umbilical vein endothelial cells (HUVECs). Metabolomic profiling further reveals AMG's capacity to alleviate MGO-induced metabolic dysregulation by modulating critical pathways, including glutathione metabolism and the TCA cycle. In diabetic mice, AMG attenuates site-specific glycation adducts on plasma albumin and demonstrates significant therapeutic efficacy by improving endothelial-dependent vasodilation via the eNOS/NO pathway, reducing vascular fibrosis and basement membrane thickening, and suppressing NF-κB-driven inflammatory responses. These integrated findings establish AMG as a promising therapeutic candidate with multifaceted protective effects against diabetic vascular injury.

1. Introduction

Diabetes is a chronic disease characterized by hyperglycemia [1]. Chronic hyperglycemia induces endothelial dysfunction, primarily through non-enzymatic glycation, a key pathogenic mechanism in diabetic vascular complications [2]. Non-enzymatic glycation is a nucleophilic addition reaction between glucose and basic amino acids of proteins [3]. This process generates highly reactive carbonyl intermediates, such as methylglyoxal (MGO), glyoxal and deoxyglucosone, which exhibit significantly greater reactivity than glucose molecules. These carbonyl compounds can rapidly react with plasma proteins to form toxic advanced glycation end products (AGEs), which accumulate in plasma and contribute to pathological effects [4].

As the predominant plasma protein, human serum albumin (HSA) undergoes substantial glycation under diabetic conditions. It constitutes over 80% of circulating glycated proteins and is the major source of AGEs in the circulation [5,6]. AGEs bind to the receptor for advanced glycation end products (RAGE) on the surface of vascular endothelial cells, activating a series of signaling pathways, including nuclear factor kappa-B (NF-κB), which culminates in apoptosis, oxidative stress, chronic inflammation, and metabolic disorders in endothelial cells [7]. These interconnected pathological mechanisms synergistically compromise vascular integrity by disrupting endothelial barrier function, reducing nitric oxide (NO) bioavailability, and impairing endothelium-dependent vasodilation, thereby promoting the progression of diabetic vascular complications [8].