Department of Clinical Pharmacy, GuangDong Pharmaceutical University, GuangZhou, China; Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Department of Clinical Pharmacy, GuangDong Pharmaceutical University, GuangZhou, China.
Biochem Pharmacol. 2020 Aug;178:114100. doi: 10.1016/j.bcp.2020.114100. Epub 2020 Jun 12.
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.
短链酰基辅酶 A 脱氢酶（SCAD）是脂肪酸β氧化的限速酶，对病理性心肌肥厚和纤维化具有负向调节作用。此外，黄素腺嘌呤二核苷酸（FAD）可以增强 SCAD 的表达和酶活性。然而，FAD 是否能抑制病理性心肌肥厚和纤维化尚不清楚。因此，我们观察了 FAD 对病理性心肌肥厚和纤维化的影响。FAD 显著抑制了 PE 诱导的心肌细胞肥大和 AngII 诱导的心肌成纤维细胞增殖。此外，FAD 改善了 SHR 的病理性心肌肥厚和纤维化。FAD 显著增加了 SCAD 的表达和酶活性。同时，FAD 增加了体内和体外的 ATP 含量，降低了游离脂肪酸和活性氧的含量。此外，分子动力学模拟也被用于提供对 SCAD 二聚体稳定性和底物催化口袋动态行为的结构稳定性和动态行为的深入了解。结果表明，FAD 可能通过激活 SCAD 对 SCAD 二聚体稳定性和维持起重要的结构作用，从而增加 SCAD 的表达和酶活性。总之，FAD 通过激活 SCAD 抑制病理性心肌肥厚和纤维化，可能成为病理性心肌肥厚和纤维化的一种新的有效治疗方法，从而防止其发展为心力衰竭。
