Diabetes mellitus (DM) is recognized as a risk factor driving atherosclerosis (AS) and cardiovascular mortality. Large-scale clinical studies have confirmed that diabetic macroangiopathy and microangiopathy are the leading causes of disability and mortality in diabetic patients. For patients with chronic long-term hyperglycaemia, the incidence of diabetic vascular complications has not decreased despite strict blood glucose and risk factors control, which is termed “metabolic memory.” Thus, to find effective targets for the prevention and treatment of diabetic angiopathy is an urgent requisite.

In the case of long-term hyperglycaemia, a large amount of advanced glycation end products (AGEs) are generated rapidly by a series of reactions, such as enzymatic saccharification and oxidative modification of proteins, lipid, and nucleic acid. Interestingly, high levels of serum AGEs and receptor for AGEs (RAGE) are associated with an increased incidence and severity of coronary artery disease (CAD) and heart failure (HF), and exogenous AGEs directly cause normal animals to produce typical vascular lesions and pathologic neovascularization.1., 2., 3. Recent studies have shown that AGEs are considered the most reasonable explanation for metabolic memory.4., 5.

The biological effects of AGEs are mainly mediated by binding to its RAGE, the combination of which induces a large number of free oxygen radicals and activates nuclear factor kappa B (NF-κB) to initiate the gene transcription of pathways related to diabetic vascular complications.6 Reportedly, the cytoplasmic domain of RAGE can bind to mDia1, which interacts with downstream molecule profilin-1 to trigger a variety of signaling pathways.7 Profilin-1 is a multi-functional actin-binding protein (12–15 kDa) with an essential role in the regulation of cytoskeleton rearrangement and redistribution by promoting actin polymerization and remodeling. Accumulating evidence has demonstrated that under pathological conditions, such as hypertension, AS, and diabetes, profilin-1 levels were markedly increased in serum, diabetic endothelium, and atherosclerotic lesions.8., 9., 10. Surprisingly, the role of profilin-1 in endothelial damage triggered by diabetic milieu was similar to that triggered by lipid oxidation,10 and the expression of profilin-1 was attenuated, which protected LDL receptor null mice from AS.11 Therefore, profilin-1 is deemed a promising therapeutic target for preventing diabetes-complicated vasculopathy.

In a previous study, we reported that AGEs induce endothelial dysfunction and cardiomyocyte hypertrophy in vitro, which is attenuated by the knockdown of profilin-1 expression.12., 13. Thus, the present study aimed to construct a model of diabetic vasculopathy, explore the role of profilin-1 in AGEs-induced vascular injury, and clarify the putative mechanism for metabolic memory mediated by AGEs.