Imbalances in RNA metabolic networks in vascular lesions associated with diabetes and sarcopenia

Figure 4 Mechanistic scheme showing how RNA metabolic imbalance aggravates vascular injury in diabetic sarcopenia. This figure is produced using Adobe Illustrator and Biorender. Hyperglycaemia induces oxidative stress and activates nuclear factor kappa B/Janus kinase - signal transducer and activator of transcription inflammatory signalling. This creates a positive feedback loop to trigger aberrant m⁶A modification and dysregulate specific mRNA stability. Reduced endothelial nitric oxide synthase mRNA expression suppresses NO production; disordered vascular endothelial growth factor/fibroblast growth factor transcripts together with disturbed long non-coding RNAs-miRNA networks promote endothelial-mesenchymal transition and endothelial dysfunction. Downregulated insulin receptor substrate 1/protein kinase B mRNA impairs insulin signalling. Decreased expression of mitochondrial biogenesis genes leads to mitochondrial dysfunction and apoptosis of vascular endothelial cells and vascular smooth muscle cell. Aberrant splicing of carnitine palmitoyltransferase 1A/acyl-CoA dehydrogenase very long chain mRNA disrupts fatty acid oxidation and causes lipid accumulation. These sequential pathological changes drive vascular remodelling and accelerate atherosclerosis. SOD: Superoxide dismutase; GPx: Glutathione peroxidase; NF-κB: Nuclear factor kappa B; JAK-STAT: Janus kinase - signal transducer and activator of transcription; VEGF: Vascular endothelial growth factor; FGF: Fibroblast growth factor; eNOS: Endothelial nitric oxide synthase; lncRNA: Long non-coding RNA; IRS-1: Insulin receptor substrate 1; AKT: Protein kinase B; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; NRF1: Nuclear respiratory factor 1; TFAM: Mitochondrial transcription factor A; CPT1A: Carnitine palmitoyltransferase 1A; ACADVL: Acyl-CoA dehydrogenase very long chain; EndMT: Endothelial-mesenchymal transition; VECs: Vascular endothelial cells; VSMCs: Vascular smooth muscle cell.