Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, Zurich University Hospital and University of Zurich, Wagistrasse 12, 8952, Schlieren, Switzerland.
Department of Cardiology, Zurich University Hospital, Zurich, Switzerland.
Cardiovasc Diabetol. 2023 Nov 13;22(1):312. doi: 10.1186/s12933-023-02057-2.
Metabolic cardiomyopathy (MCM), characterized by intramyocardial lipid accumulation, drives the progression to heart failure with preserved ejection fraction (HFpEF). Although evidence suggests that the mammalian silent information regulator 1 (Sirt1) orchestrates myocardial lipid metabolism, it is unknown whether its exogenous administration could avoid MCM onset. We investigated whether chronic treatment with recombinant Sirt1 (rSirt1) could halt MCM progression.
db/db mice, an established model of MCM, were supplemented with intraperitoneal rSirt1 or vehicle for 4 weeks and compared with their db/ + heterozygous littermates. At the end of treatment, cardiac function was assessed by cardiac ultrasound and left ventricular samples were collected and processed for molecular analysis. Transcriptional changes were evaluated using a custom PCR array. Lipidomic analysis was performed by mass spectrometry. H9c2 cardiomyocytes exposed to hyperglycaemia and treated with rSirt1 were used as in vitro model of MCM to investigate the ability of rSirt1 to directly target cardiomyocytes and modulate malondialdehyde levels and caspase 3 activity. Myocardial samples from diabetic and nondiabetic patients were analysed to explore Sirt1 expression levels and signaling pathways.
rSirt1 treatment restored cardiac Sirt1 levels and preserved cardiac performance by improving left ventricular ejection fraction, fractional shortening and diastolic function (E/A ratio). In left ventricular samples from rSirt1-treated db/db mice, rSirt1 modulated the cardiac lipidome: medium and long-chain triacylglycerols, long-chain triacylglycerols, and triacylglycerols containing only saturated fatty acids were reduced, while those containing docosahexaenoic acid were increased. Mechanistically, several genes involved in lipid trafficking, metabolism and inflammation, such as Cd36, Acox3, Pparg, Ncoa3, and Ppara were downregulated by rSirt1 both in vitro and in vivo. In humans, reduced cardiac expression levels of Sirt1 were associated with higher intramyocardial triacylglycerols and PPARG-related genes.
In the db/db mouse model of MCM, chronic exogenous rSirt1 supplementation rescued cardiac function. This was associated with a modulation of the myocardial lipidome and a downregulation of genes involved in lipid metabolism, trafficking, inflammation, and PPARG signaling. These findings were confirmed in the human diabetic myocardium. Treatments that increase Sirt1 levels may represent a promising strategy to prevent myocardial lipid abnormalities and MCM development.
代谢性心肌病（MCM）的特征是心肌内脂质堆积，导致射血分数保留的心力衰竭（HFpEF）进展。尽管有证据表明哺乳动物沉默信息调节因子 1（Sirt1）协调心肌脂质代谢，但尚不清楚其外源性给药是否可以避免 MCM 的发生。我们研究了慢性给予重组 Sirt1（rSirt1）是否可以阻止 MCM 的进展。
将 db/db 小鼠（MCM 的一种已建立模型）腹腔内补充 rSirt1 或载体 4 周，并与 db/+ 杂合子同窝仔鼠进行比较。在治疗结束时，通过心脏超声评估心功能，并采集左心室样本进行分子分析。使用定制的 PCR 阵列评估转录变化。通过质谱法进行脂质组学分析。将暴露于高血糖的 H9c2 心肌细胞与 rSirt1 一起处理，用作 MCM 的体外模型，以研究 rSirt1 直接靶向心肌细胞和调节丙二醛水平和 caspase 3 活性的能力。分析糖尿病和非糖尿病患者的心肌样本以探索 Sirt1 表达水平和信号通路。
rSirt1 治疗通过改善左心室射血分数、缩短分数和舒张功能（E/A 比值）恢复了心脏 Sirt1 水平并维持了心脏功能。在 rSirt1 治疗的 db/db 小鼠的左心室样本中，rSirt1 调节了心脏脂质组：中链和长链三酰甘油、长链三酰甘油和仅含饱和脂肪酸的三酰甘油减少，而含二十二碳六烯酸的三酰甘油增加。在体外和体内，rSirt1 下调了几个参与脂质转运、代谢和炎症的基因，如 Cd36、Acox3、Pparg、Ncoa3 和 Ppara。在人类中，心脏 Sirt1 表达水平降低与心肌内三酰甘油和与 PPARG 相关基因的升高有关。
在 MCM 的 db/db 小鼠模型中，慢性外源性 rSirt1 补充挽救了心功能。这与心肌脂质组的调节以及参与脂质代谢、转运、炎症和 PPARG 信号的基因的下调有关。这些发现在人类糖尿病心肌中得到了证实。增加 Sirt1 水平的治疗方法可能是预防心肌脂质异常和 MCM 发展的有前途的策略。
