SIRT6 Mitigates Heart Failure With Preserved Ejection Fraction in Diabetes.
SIRT6 Mitigates Heart Failure With Preserved Ejection Fraction in Diabetes.
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DOI：
10.1161/circresaha.121.318988
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发表时间：
2022-11-11
影响因子：
20.1
通讯作者：
Jin, Zheng Gen
中科院分区：
文献类型：
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作者：
Wu, Xiaoqian;Liu, Huan;Brooks, Alan;Xu, Suowen;Luo, Jinque;Steiner, Rebbeca;Mickelsen, Deanne M.;Moravec, Christine S.;Jeffrey, Alexis D.;Small, Eric M.;Jin, Zheng Gen
心力衰竭(HF)伴保留射血分数(HFpEF)是一个日益严重的健康问题，缺乏有效的治疗方法。流行病学研究表明，糖尿病是HFpEF的强烈危险因素，约45%的HFpEF患者患有糖尿病。然而，糖尿病与HFpEF相关的分子机制却知之甚少。本研究旨在探讨长寿基因sirtuin6(SIRT6)是否能调节内皮脂肪酸(FA)的转运，改善糖尿病大鼠的HFpEF。我们首次观察到，在长期高脂饮食和一次低剂量链脲佐菌素攻击的组合下，糖尿病心衰患者和伴有HFpEF各种症状的糖尿病小鼠的心脏组织内皮细胞SIRT6的表达显著减少。然后我们建立了一个独特的人源化SIRT6转基因小鼠模型，在该模型中，在小鼠的rosa26基因座上进行了单拷贝的人SIRT6转基因基因的工程，并用Cre-loxP技术进行了条件诱导。我们发现，通过基因恢复糖尿病小鼠内皮细胞SIRT6的表达，可以改善舒张期功能障碍，同时减少心脏脂肪堆积。SIRT6功能增减研究表明，SIRT6负性调节内皮FA摄取。机制上，SIRT6通过依赖SIRT6依赖于PPARγ启动子区域H3K9的脱乙酰化来抑制内皮细胞PPARγ的表达，而PPARγ下调介导依赖于SIRT6的内皮FA摄取抑制。重要的是，口服小分子SIRT6激活剂MDL-800给糖尿病小鼠缓解了心脏脂质堆积和舒张期功能障碍。内皮细胞SIRT6表达受损通过改变FA跨内皮屏障的转运，将糖尿病与HFpEF联系起来。糖尿病患者恢复内皮细胞SIRT6功能的遗传和药物策略通过限制FA超负荷和改善心脏代谢而减轻实验性HFpEF，因此有必要进行进一步的临床评估。
Heart failure (HF) with preserved ejection fraction (HFpEF) is a growing health problem without effective therapies. Epidemiological studies indicate that diabetes is a strong risk factor for HFpEF, and about 45% of patients with HFpEF are suffering from diabetes. However, the molecular mechanisms for the association of diabetes and HFpEF are poorly understood. This study was designed to explore whether the longevity gene sirtuin 6 (SIRT6) could regulate endothelial fatty acid (FA) transport and ameliorate HFpEF in diabetes. We first observed that endothelial SIRT6 expression was markedly diminished in cardiac tissues from HF patients with diabetes and diabetic mice with the myriad symptoms of HFpEF, which was induced by the combination of the long-term high-fat diet and one low-dose streptozocin challenge. We then generated a unique humanized SIRT6 transgenic mouse model, in which a single copy of human SIRT6 transgene was engineered at mouse Rosa26 locus and conditionally induced with the Cre-loxP technology. We found that genetically restoring endothelial SIRT6 expression in the diabetic mice ameliorated diastolic dysfunction concurrently with decreased cardiac lipid accumulation. SIRT6 gain- or loss-of-function studies showed that SIRT6 negatively regulated endothelial FA uptake. Mechanistically, SIRT6 suppressed endothelial expression of PPARγ through SIRT6-dependent deacetylation of H3K9 around PPARγ promoter region; and PPARγ downregulation mediated SIRT6-dependent inhibition of endothelial FA uptake. Importantly, oral administration of small molecule SIRT6 activator MDL-800 to diabetic mice mitigated cardiac lipid accumulation and diastolic dysfunction. The impairment of endothelial SIRT6 expression links diabetes to HFpEF through altering FA transport across the endothelial barrier. The genetic and pharmacological strategies that restore endothelial SIRT6 function in diabetes alleviated experimental HFpEF by limiting FA overtake and improving cardiac metabolism, thus warranting further clinical evaluation.