Chronic hyperglycemia and cardiovascular dysfunction: an in-depth exploration of metabolic and cellular pathways in...

Chronic hyperglycemia is the defining feature of type 2 diabetes mellitus (T2DM) and a central driver of its long-term complications, including microvascular and macrovascular diseases. Among these, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in individuals with T2DM. Persistent glucose elevation activates multiple interrelated biochemical pathways, including the polyol pathway, formation of advanced glycation end-products, protein kinase C activation, oxidative stress via several cellular mechanisms, as well as the hexosamine biosynthetic pathway. These processes collectively promote excessive oxidative damage, endothelial dysfunction, inflammation, and adverse cardiac remodeling, ultimately accelerating cardiovascular damage. Research has further revealed that hyperglycemia imprints long-lasting molecular changes through metabolic memory, largely mediated by epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs, and sustaining vascular dysfunction even after glycemic control. Building on both classical and emerging evidence, this review synthesizes advances in understanding hyperglycemia-induced vascular damage and highlights promising therapeutic targets within these pathways. Strategies under investigation include inhibitors of enzymatic reactive oxygen species sources, modulators of mitochondrial dynamics and function, regulators of protein kinase C, blockers of glycation pathways, and epidrugs targeting epigenetic modifications. By integrating these mechanistic insights with therapeutic innovation, the field is shifting from a narrow focus on glucose lowering to a broader approach aimed at preventing and potentially reversing the vascular complications of diabetes. This perspective emphasizes the urgent need for pathway-specific therapeutic strategies to effectively address the cardiovascular burden of T2DM.