Riboflavin protects against heart failure via SCAD‐dependent DJ‐1–Keap1–Nrf2 signalling pathway

Abstract

Background and PurposeOur recent studies have shown that flavin adenine dinucleotide (FAD) exerts cardiovascular protective effects by supplementing short‐chain acyl‐CoA dehydrogenase (SCAD). The current study aimed to elucidate whether riboflavin (the precursor of FAD) could improve heart failure via activating SCAD and the DJ‐1–Keap1–Nrf2 signalling pathway.Experimental ApproachRiboflavin treatment was given to the mouse transverse aortic constriction (TAC)‐induced heart failure model. Cardiac structure and function, energy metabolism and apoptosis index were assessed, and relevant signalling proteins were analysed. The mechanisms underlying the cardioprotection by riboflavin were analysed in the cell apoptosis model induced by tert‐butyl hydroperoxide (tBHP).Key ResultsIn vivo, riboflavin ameliorated myocardial fibrosis and energy metabolism, improved cardiac dysfunction and inhibited oxidative stress and cardiomyocyte apoptosis in TAC‐induced heart failure. In vitro, riboflavin ameliorated cell apoptosis in H9C2 cardiomyocytes by decreasing reactive oxygen species (ROS). At the molecular level, riboflavin significantly restored FAD content, SCAD expression and enzymatic activity, activated DJ‐1 and inhibited the Keap1–Nrf2/HO1 signalling pathway in vivo and in vitro. SCAD knockdown exaggerated the tBHP‐induced DJ‐1 decrease and Keap1–Nrf2/HO1 signalling pathway activation in H9C2 cardiomyocytes. The knockdown of SCAD abolished the anti‐apoptotic effects of riboflavin on H9C2 cardiomyocytes. DJ‐1 knockdown hindered SCAD overexpression anti‐apoptotic effects and regulation on Keap1–Nrf2/HO1 signalling pathway in H9C2 cardiomyocytes.Conclusions and ImplicationsRiboflavin exerts cardioprotective effects on heart failure by improving oxidative stress and cardiomyocyte apoptosis via FAD to stimulate SCAD and then activates the DJ‐1–Keap1–Nrf2 signalling pathway.

New Insights into Radio-Resistance Mechanism Revealed by (Phospho)Proteome Analysis of Deinococcus Radiodurans after Heavy Ion Irradiation

“…In the antioxidant pathways, such as alpha-linolenic acid metabolism, phenylalanine metabolism, and riboflavin metabolism, the levels of protein expression and phosphorylation were all upregulated to different extents (Figure 3A). These pathways may help to clear radiationgenerated ROS and maintain cellular homeostasis [44][45][46]. Notably, 20 of the 29 identified proteins in the oxidative phosphorylation pathway were upregulated, including multiple subunits of NADH dehydrogenase and V-type ATP synthase, and cytochrome c oxidase (Table S3B).…”