Department of Cardiology/Cardiac Catheterization Lab, The Second Xiangya Hospital, Central South University, No.139 Middle Renmin Road, Furong District, Changsha, 410011, Hunan, China.
Lipids Health Dis. 2019 May 10;18(1):109. doi: 10.1186/s12944-019-1059-7.
Atrial lipid metabolic remodeling is critical for the process of atrial fibrillation (AF). Abnormal Fatty acid (FA) metabolism in cardiomyocytes is involved in the pathogenesis of AF. MET (Metformin), an AMPK (AMP-activated protein kinase) activator, has been found to be associated with a decreased risk of AF in patients with type 2 diabetes. However, the specific mechanism remains unknown.
Fifteen mongrel dogs were divided into three groups: SR, ARP (pacing with 800 beats/min for 6 h), ARP plus MET (treated with MET (100 mg/kg/day) for two weeks before pacing). We assessed metabolic factors, speed limiting enzymes circulating biochemical metabolites (substrates and products), atrial electrophysiology and accumulation of lipid droplets.
The expression of AMPK increased in the ARP group and significantly increased in the MET+ARP group comparing to the SR group. In the ARP group, the expressions of PPARα、PGC-1α and VLCAD were down-regulated, while the concentration of free fatty acid and triglyceride and the lipid deposition in LAA (left atrial appendage) increased. Moreover, AERP and AERPd have also been found abnormally in this process. Pretreatment with MET before receiving ARP reversed the alterations aforementioned.
The FA metabolism in LAA is altered in the ARP group, mainly characterized by the abnormal expression of the rate-limiting enzyme. Metformin reduces lipid accumulation and promotes β-oxidation of FA in AF models partially through AMPK/PPAR-α/VLCAD pathway. Our study indicates that MET may inhibit the FA lipid metabolic remodeling in AF.
心房脂质代谢重塑对于心房颤动（AF）的发生过程至关重要。心肌细胞中脂肪酸（FA）代谢异常参与了 AF 的发病机制。二甲双胍（MET）是一种 AMPK（AMP 激活蛋白激酶）激活剂，已被发现与 2 型糖尿病患者 AF 风险降低相关。然而，其具体机制尚不清楚。
将 15 只杂种犬分为三组：窦性心律组（SR）、心房快速起搏组（ARP，以 800 次/分起搏 6 小时）、心房快速起搏加 MET 组（ARP 前两周给予 MET（100mg/kg/天）治疗）。我们评估了代谢因素、循环生化代谢物限速酶（底物和产物）、心房电生理和脂滴蓄积。
与 SR 组相比，ARP 组中 AMPK 的表达增加，而 MET+ARP 组中 AMPK 的表达显著增加。在 ARP 组中，PPARα、PGC-1α 和 VLCAD 的表达下调，而游离脂肪酸和甘油三酯的浓度以及左心耳（LAA）的脂质沉积增加。此外，在这个过程中还发现 AERP 和 AERPd 异常。在接受 ARP 前用 MET 预处理可逆转上述改变。
ARP 组 LAA 中的 FA 代谢发生改变，主要表现为限速酶的异常表达。二甲双胍通过 AMPK/PPAR-α/VLCAD 通路减少 AF 模型中的脂质堆积并促进 FA 的β氧化。我们的研究表明，MET 可能抑制 AF 中 FA 脂质代谢重塑。
