Department of Cardiology, the First Affiliated Hospital, Harbin Medical University, Youzheng Street 23#, Nangang District, Harbin, 150001, Heilongjiang Province, China.
Centre for Drug Safety Evaluation, Heilongjiang University of Chinese Medicine, Harbin, 150001, Heilongjiang Province, China.
Naunyn Schmiedebergs Arch Pharmacol. 2019 Jul;392(7):851-863. doi: 10.1007/s00210-019-01641-2. Epub 2019 Mar 9.
Aldosterone (Aldo), a pivotal hormone that is ubiquitously expressed in systemic tissues of mammals, is a crucial factor in the pathogenesis of cardiac disease. Accumulating evidence suggests that disturbances in cell energy metabolism are involved in increasing aldosterone levels. However, the precise mechanism underlying the impact of cardiac metabolic remodeling underlying aldosterone stimulation remains limited. In this work, we evaluated the underlying effect of aldosterone on regulating cardiac metabolism remodeling in a canine model. Fifteen beagle dogs were divided into a control group (n = 5), Aldo group (n = 5), and a group treated with spironolactone (SP), a mineralocorticoid receptor antagonist (n = 5), for 4 weeks. Blood pressure, electrocardiogram and respiratory parameters, H&E, Masson staining, ultrastructural changes, the adenosine triphosphate (ATP) and free fatty acid (FFA) levels of ventricular tissues, the level of mRNA, and the protein expression of key metabolic factors and regulators were assessed. The Sirt1/AMPK signaling pathway was significantly inhibited in the canine model of aldosterone stimulation, resulting in a reduction of the key downstream metabolic factors involved in glucose and fatty acid oxidation. The dysregulation of expression of key factors in glycogen metabolism led to glycogen deposition, an increase in FFA levels, a reduction in ATP levels, apoptosis, inflammatory cell infiltration, and mitochondrial damage in the ventricular myocardium. These effects were significantly restored by spironolactone. Aldosterone stimulation induced cardiac metabolic remodeling in ventricular cardiomyocytes possibly through the Sirt1/AMPK signaling pathway, implying that this pathway may provide a novel therapeutic target for cardiac metabolic remodeling.
醛固酮（Aldo）是一种广泛表达于哺乳动物全身组织的关键激素，是心脏病发病机制中的重要因素。越来越多的证据表明，细胞能量代谢紊乱参与了醛固酮水平的升高。然而，醛固酮刺激导致心脏代谢重构的具体机制仍十分有限。在这项工作中，我们评估了醛固酮对犬模型心脏代谢重构的潜在影响。将 15 只比格犬分为对照组（n = 5）、Aldo 组（n = 5）和螺内酯（SP）组（n = 5），SP 是一种盐皮质激素受体拮抗剂，治疗 4 周。评估血压、心电图和呼吸参数、H&E、Masson 染色、超微结构变化、心室组织的三磷酸腺苷（ATP）和游离脂肪酸（FFA）水平、关键代谢因子和调节剂的 mRNA 水平以及蛋白表达。醛固酮刺激犬模型中 Sirt1/AMPK 信号通路受到显著抑制，导致参与葡萄糖和脂肪酸氧化的关键下游代谢因子减少。糖原代谢关键因子表达失调导致糖原沉积、FFA 水平升高、ATP 水平降低、凋亡、炎症细胞浸润和心室心肌线粒体损伤。螺内酯可显著恢复这些变化。醛固酮刺激可能通过 Sirt1/AMPK 信号通路诱导心室肌细胞心脏代谢重构，这表明该通路可能为心脏代谢重构提供一个新的治疗靶点。
