Riboflavin protects against heart failure via SCAD-dependent DJ-1- Keap1-Nrf2 signaling pathway

• Published in: British journal of pharmacology 2023-12, Vol.180 (23), p.3024-3044
• Main Authors: Xu, Qingping, Cao, Yuhong, Zhong, Xiaoyi, Qin, Xue, Feng, Jingyun, Peng, Huan, Su, Yongshao, Ma, Zhichao, Zhou, Sigui
• Format: Article
• Language: English
• Subjects: Aorta; Apoptosis; Butyl hydroperoxide; Cardiomyocytes; Congestive heart failure; Energy metabolism; Enzymatic activity; Fibrosis; Flavin; Flavin-adenine dinucleotide; Heart failure; Metabolism; Oxidative stress; Reactive oxygen species; Riboflavin; Signal transduction; Structure-function relationships; Vitamin B
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.16184

Our 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 DJ-1- Keap1-Nrf2 signaling pathway. Riboflavin treatment was performed in mice's transverse aortic constriction (TAC)-induced heart failure model. Cardiac structure and function, energy metabolism and apoptosis index were assessed, and relevant signaling proteins were analyzed. The mechanisms underlying the cardio-protection of riboflavin were analyzed in the cell apoptosis model induced by tert-butyl hydroperoxide (tBHP). The apoptosis index and signaling proteins were analyzed. In 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 Keap1-Nrf2/HO-1 signaling pathway in vivo and in vitro. SCAD knockdown exaggerated tBHP-induced DJ-1 decrease and Keap1-Nrf2/HO-1 signaling pathway activation in H9C2 cardiomyocytes. The knockdown of SCAD abolished the anti-apoptotic effects of riboflavin on H9C2 cardiomyocytes. Furthermore, DJ-1 knockdown hindered SCAD overexpression anti-apoptotic effects and regulation on Keap1-Nrf2/HO-1 signaling pathway in H9C2 cardiomyocytes. Riboflavin exerts cardioprotective effects on heart failure by improving oxidative stress and cardiomyocyte apoptosis via adding FAD to stimulate SCAD, then activates the DJ-1-Keap1-Nrf2 signaling pathway.