Lymphatic Endothelial Branched-Chain Amino Acid Catabolic Defects Undermine Cardiac Lymphatic Integrity and Drive HFpEF

• DOI: 10.1161/circulationaha.124.071741
• Publication Date: 2025-04-01T09:05:55Z
• Authors: Xiong Guo; Chong Huang; Ling Zhang; Guangyu Hu; Yunhui Du; Xiyao Chen; Fangfang Sun; Tongzheng Li; Zhe Cui; Congye Li; Yongzhen Guo; Wenjun Yan; Yunlong Xia; Shan Wang; Hui Liu; Zhiyuan Liu; Zhen Lin; Xinyi Wang; Zhengyang Wang; Fuyang Zhang; Ling Tao
• Keywords: Catabolism; Lymphatic Endothelium; Lymphangiogenesis

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, but effective treatments are lacking. Cardiac lymphatics play a crucial role in maintaining health by draining fluids and immune cells. However, their involvement HFpEF remains largely unexplored. METHODS: We examined cardiac lymphatic alterations mice comorbid obesity hypertension, tissues from patients HFpEF. Using genetically engineered mouse models various cellular molecular techniques, we investigated underlying mechanisms. RESULTS: In HFpEF, displayed substantial structural functional anomalies, including decreased endothelial cell (LEC) density, vessel fragmentation, reduced branch connections, impaired capacity to drain LEC numbers marker expression levels were also Stimulating lymphangiogenesis an adeno-associated virus expressing variant vascular growth factor C (VEGFC C156S ) that selectively activates receptor 3 (VEGFR3) LECs restored integrity substantially alleviated Through discovery-driven approaches, defective branched-chain amino acid (BCAA) catabolism was identified as predominant metabolic signature LECs. Overexpression ketoacid dehydrogenase kinase (encoded Bckdk gene), which inactivates (the rate-limiting enzyme BCAA catabolism), resulted spontaneous lymphangiogenic defects mice, inducible gene deletion enhance protected against catabolic caused ligand-independent phosphorylation VEGFR3 cytoplasm Src kinase, leading lysosomal degradation instead its trafficking membrane. Reduced availability on surface impeded downstream Akt (protein B) activation, hindered glucose uptake utilization, inhibited defects. CONCLUSIONS: Our study provides evidence disruption, driven LECs, is key contributing These findings unravel modulating biology, suggest preserving may present novel therapeutic strategy for