Wu Jian, Lu Jing, Huang Jiayuan, You Jieyun, Ding Zhiwen, Ma Leilei, Dai Fangjie, Xu Ran, Li Xuan, Yin Peipei, Zhao Gang, Wang Shijun, Yuan Jie, Yang Xiangdong, Ge Junbo, Zou Yunzeng
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Key Laboratory of Guangdong Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, China.
Front Cardiovasc Med. 2020 Dec 11;7:602100. doi: 10.3389/fcvm.2020.602100. eCollection 2020.
Recent studies have unveiled that myocardial hypertrophic preconditioning (HP), which is produced by de-banding (De-TAC) of short-term transverse aortic constriction (TAC), protects the heart against hypertrophic responses caused by subsequent re-constriction (Re-TAC) in mice. Although cardiac substrate metabolism is impaired in heart failure, it remains unclear about the role of HP-driven energetics in the development of cardiac hypertrophy. Here, we investigated energy metabolism, cardiac hypertrophy, and function following variational loading conditions, as well as their relationships in HP. Male C57BL/6J mice (10-12 weeks old) were randomly subjected to Sham, HP [TAC for 3days (TAC 3d), de-banding the aorta for 4 days (De-TAC 4d), and then re-banding the aorta for 4 weeks (Re-TAC 4W)], and TAC (TAC for 4 weeks without de-banding). Cardiac echocardiography, hemodynamics, and histology were utilized to evaluate cardiac remodeling and function. The mRNA expression levels of fetal genes ( and ), glucose metabolism-related genes (), and fatty acid oxidation-related genes (α, α) were quantitated by real-time quantitative PCR. Activation of hypertrophy regulators ERK1/2, a metabolic stress kinase AMP-activated protein kinase (AMPK), and its downstream target acetyl-coA carboxylase (ACC) were explored by western blot. Compared with TAC 4W mice, Re-TAC 4W mice showed less impairment in glucose and fatty acid metabolism, as well as less cardiac hypertrophy and dysfunction. Moreover, no significant difference was found in myocardial hypertrophy, fibrosis, and cardiac function in TAC 3d and De-TAC 4d groups compared with Sham group. However, α, , and α were all decreased, while AMPK and ACC were activated in TAC 3d and returned to Sham level in De-TAC 4d, suggesting that the change in myocardial energy metabolism in HP mice was earlier than that in cardiac structure and function. Collectively, HP improves energy metabolism and delays cardiac remodeling, highlighting that early metabolic improvements drive a potential beneficial effect on structural and functional restoration in cardiac hypertrophy.
最近的研究表明，通过短期横向主动脉缩窄（TAC）解除缩窄（去带，De-TAC）所产生的心肌肥厚预处理（HP），可保护小鼠心脏免受随后再次缩窄（再缩窄，Re-TAC）所引起的肥厚反应。尽管心力衰竭时心脏底物代谢受损，但HP驱动的能量学在心肌肥厚发展中的作用仍不清楚。在此，我们研究了不同负荷条件下的能量代谢、心肌肥厚及功能，以及它们在HP中的关系。将雄性C57BL/6J小鼠（10 - 12周龄）随机分为假手术组、HP组【TAC 3天（TAC 3d），主动脉去带4天（De-TAC 4d），然后主动脉再次缩窄4周（Re-TAC 4W）】和TAC组（TAC 4周，不进行去带）。利用心脏超声心动图、血流动力学和组织学评估心脏重塑和功能。通过实时定量PCR定量检测胎儿基因（和）、葡萄糖代谢相关基因（）以及脂肪酸氧化相关基因（α、α）的mRNA表达水平。通过蛋白质免疫印迹法探究肥厚调节因子细胞外信号调节激酶1/2（ERK1/2）、代谢应激激酶腺苷酸活化蛋白激酶（AMPK）及其下游靶点乙酰辅酶A羧化酶（ACC）的激活情况。与TAC 4W小鼠相比，Re-TAC 4W小鼠在葡萄糖和脂肪酸代谢方面的损伤较小，心肌肥厚和功能障碍也较轻。此外，与假手术组相比，TAC 3d组和De-TAC 4d组在心肌肥厚、纤维化和心脏功能方面无显著差异。然而，α、和α均降低，而AMPK和ACC在TAC 3d时被激活，并在De-TAC 4d时恢复到假手术组水平，这表明HP小鼠心肌能量代谢的变化早于心脏结构和功能的变化。总体而言，HP改善能量代谢并延缓心脏重塑，突出了早期代谢改善对心肌肥厚结构和功能恢复的潜在有益作用。
