flavin-adenine-dinucleotide and Heart-Failure

Topics: Animals; Cardiovascular Diseases; Communicable Diseases; Eye Diseases; Female; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Heart Failure; Humans; Hyperbaric Oxygenation; Nutritional Requirements; Postoperative Complications; Pregnancy; Pregnancy Complications; Rheumatic Fever; Riboflavin; Riboflavin Deficiency; Skin Diseases; Stomach Diseases

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 the DJ-1-Keap1-Nrf2 signalling pathway.. Riboflavin 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).. 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 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.. Riboflavin 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.

Topics: Animals; Apoptosis; Butyryl-CoA Dehydrogenase; Flavin-Adenine Dinucleotide; Heart Failure; Kelch-Like ECH-Associated Protein 1; Mice; Myocytes, Cardiac; NF-E2-Related Factor 2; Oxidative Stress

Short-chain acyl-CoA dehydrogenase (SCAD), the rate-limiting enzyme for fatty acid β-oxidation, has a negative regulatory effect on pathological cardiac hypertrophy and fibrosis. Furthermore, flavin adenine dinucleotide (FAD) can enhance the expression and enzyme activity of SCAD. However, whether FAD can inhibit pathological cardiac hypertrophy and fibrosis remains unclear. Therefore, we observed the effect of FAD on pathological cardiac hypertrophy and fibrosis. FAD significantly inhibited PE-induced cardiomyocyte hypertrophy and AngII-induced cardiac fibroblast proliferation. In addition, FAD ameliorated pathological cardiac hypertrophy and fibrosis in SHR. FAD significantly increased the expression and enzyme activity of SCAD. Meanwhile, ATP content was increased, the content of free fatty acids and reactive oxygen species were decreased by FAD in vivo and in vitro. In addition, molecular dynamics simulations were also used to provide insights into the structural stability and dynamic behavior of SCAD. The results demonstrated that FAD may play an important structural role on the SCAD dimer stability and maintenance of substrate catalytic pocket to increase the expression and enzyme activity of SCAD. In conclusion, FAD can inhibit pathological cardiac hypertrophy and fibrosis through activating SCAD, which may be a novel effective treatment for pathological cardiac hypertrophy and fibrosis, thus prevent them from developing into heart failure.

Topics: Adenosine Triphosphate; Animals; Binding Sites; Butyryl-CoA Dehydrogenase; Cardiomegaly; Cardiotonic Agents; Cell Proliferation; Energy Metabolism; Enzyme Stability; Fatty Acids, Nonesterified; Fibroblasts; Fibrosis; Flavin-Adenine Dinucleotide; Gene Expression Regulation; Heart Failure; Male; Molecular Dynamics Simulation; Myocardium; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Protein Multimerization; Rats; Rats, Inbred SHR; Rats, Wistar; Reactive Oxygen Species

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Biochemical Phenomena; Biochemistry; Cardiomegaly; Chromatography; Coenzymes; Creatine; Creatinine; Cytosine Nucleotides; Dogs; Flavin-Adenine Dinucleotide; Guanine Nucleotides; Heart Failure; Metabolism; Myocardium; NAD; Nucleotides; Phosphates; Phosphocreatine; Pulmonary Valve Stenosis; Purines; Pyrimidine Nucleotides; Research; Uracil Nucleotides