l-Arginine in diabetic cardiomyopathy: Mechanistic insights into RAGE-NF-κB-SREBP1 signaling

In diabetes, glycation exacerbates low-grade inflammation and lipotoxicity, driving the development and progression of diabetic cardiomyopathy (DCM). l-Arginine (L-Arg) supplementation is crucial in the management of diabetes and cardiovascular diseases. Our previous study demonstrated the anti-glycation and antioxidant activity of L-Arg through the regulation of nuclear factor erythroid 2-related factor 2 signaling. However, the mechanistic action of L-Arg in the pathogenesis of glycation-induced DCM remains unexplored. This study elucidates the regulatory actions of L-Arg in DCM through intracellular glycation, inflammation, and lipid accumulation related receptor for advanced glycation end products (RAGE)-nuclear factor kappa-light-chain-enhanced of activated B cells (NF-κB)-sterol regulatory element binding protein 1 (SREBP1) signaling pathway. For this, H9c2 cardiomyocytes were treated with glycated human serum albumin alone or in combination with L-Arg (0.4 and 0.8 mM), FPS-ZM1 (RAGE antagonist), and fatostatin (SREBP1 inhibitor) for 24 h. It was observed that L-Arg inhibited the formation of intracellular advanced glycation end products, as well as RAGE gene and protein expressions, thereby affecting NF-κB nuclear translocation and its transcriptional activity. Consequent downregulation of NF-κB further attenuated inflammasome activation, inflammatory cytokine secretion, and apoptotic shift in L-Arg-treated cardiomyocytes. Furthermore, L-Arg treatment alleviated SREBP cleavage-activating protein (SCAP)- SREBP1 expression, resulting in suppressed lipogenic gene expression and intracellular lipid accumulation. Both inhibitors exerted similar regulatory effects on the RAGE-NF-κB-SREBP1 axis, suggesting a mechanistic overlap with L-Arg. Taken together, L-Arg ameliorated RAGE-NF-κB-SREBP1 signaling, demonstrating its therapeutic potential in the pathogenesis of glycation-induced DCM.