美国西北大学Hossein Ardehali团队报道了蛋白O-GlcNA酰化和己糖激酶线粒体解离驱动射血分数保持不变的心力衰竭。相关论文发表在2025年4月22日出版的《细胞—代谢》杂志上。

研究小组报道了HFpEF的motheme模型，并表明内皮细胞（ECs）中的己糖激酶(HK)-1线粒体结合对蛋白O-GlcNA酰化和HFpEF的发展至关重要。该研究组发现HFpEF小鼠ECs中HK1线粒体脱位增加。缺失HK1线粒体结合域的小鼠会自发发生HFpEF，并表现出血管生成受损。错位的HK1和O-连接的N-乙酰氨基葡萄糖转移酶（OGT）的空间接近增加了OGT的活性，将己糖胺生物合成途径中间体的平衡转移到O-GlcNA酰化机制中。EC特异性的O-GlcNAcase和OGT抑制剂的过表达逆转血管生成缺陷和HFpEF表型，突出了蛋白O-GlcNA酰化在HFpEF发展中的重要性。他们的研究通过HK1细胞定位和由此产生的蛋白O-GlcNA酰化证明了HFpEF的新机制，并为HFpEF提供了潜在的治疗方法。

据了解，心力衰竭伴保留射血分数（HFpEF）是世界范围内发病率和死亡率的常见主题，但其病理生理机制尚不清楚。

附：英文原文

Title: Protein O-GlcNAcylation and hexokinase mitochondrial dissociation drive heart failure with preserved ejection fraction

Author: Yuki Tatekoshi, Amir Mahmoodzadeh, Jason S. Shapiro, Mingyang Liu, George M. Bianco, Ayumi Tatekoshi, Spencer Duncan Camp, Adam De Jesus, Navid Koleini, Santiago De La Torre, J. Andrew Wasserstrom, Wolfgang H. Dillmann, Benjamin R. Thomson, Kenneth C. Bedi, Kenneth B. Margulies, Samuel E. Weinberg, Hossein Ardehali

Issue&Volume: 2025-04-22

Abstract: Heart failure with preserved ejection fraction (HFpEF) is a common cause of morbidity and mortality worldwide, but its pathophysiology remains unclear. Here, we report a mouse model of HFpEF and show that hexokinase (HK)-1 mitochondrial binding in endothelial cells (ECs) is critical for protein O-GlcNAcylation and the development of HFpEF. We demonstrate increased mitochondrial dislocation of HK1 within ECs in HFpEF mice. Mice with deletion of the mitochondrial-binding domain of HK1 spontaneously develop HFpEF and display impaired angiogenesis. Spatial proximity of dislocated HK1 and O-linked N-acetylglucosamine transferase (OGT) causes increased OGT activity, shifting the balance of the hexosamine biosynthetic pathway intermediates into the O-GlcNAcylation machinery. EC-specific overexpression of O-GlcNAcase and an OGT inhibitor reverse angiogenic defects and the HFpEF phenotype, highlighting the importance of protein O-GlcNAcylation in the development of HFpEF. Our study demonstrates a new mechanism for HFpEF through HK1 cellular localization and resultant protein O-GlcNAcylation, and provides a potential therapy for HFpEF.

DOI: 10.1016/j.cmet.2025.04.001

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00211-6