BCAA catabolism targeted therapy for heart failure with preserved ejection fraction

作者：Meng Wang, Zhao Liu, Shuxun Ren, Jinyun Zhu, Norihiko Morisawa, Geok Lin Chua, Xuewen Zhang, Yun Ka Wong, Liping Su, Ming Xiang Wong, Jieping Yang, Marc Titze Jens, Zhaoping Li, Haipeng Sun, Yibin Wang, Christoph D. Raul, Sanjiv J. Shah, Chen Gao, Yunxia Liu · 发表于：Theranostics · 年份：2025 · DOI：10.7150/thno.105894 · 被引用次数：14 · 研究领域：Fuel Cells and Related Materials、Innovative Microfluidic and Catalytic Techniques Innovation、Extraction and Separation Processes

Rationale: Heart failure with preserved ejection fraction (HFpEF) is a major unmet medical need with limited effective treatments.A significant contributing factor to HFpEF, a multifactorial disease, is underlying metabolic dysfunction.While much of the prior research has been on glucose and fatty acid metabolic defects in the pathogenesis of HFpEF, other metabolic activities remain under investigated.Methods: System-based metabolomics and targeted mass spectrometry were employed to analyze serum and tissue samples from a deep-phenotyped human HFpEF cohort.A preclinical mouse model of HFpEF was developed by combined administration of a high-fat diet (HFD) and the nitric oxide (NO) synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME).The branched-chain amino acid (BCAA) catabolic activities were enhanced by genetic inactivation of branched-chain ketoacid-dehydrogenase kinase (BCKDK) or treatment with BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid), a highly selective inhibitor of BCKDK.Cardiac function, myocardial remodeling and insulin signaling in the left ventricle were assessed across all experimental cohorts.Results: The systems-based metabolomics analysis of the deep-phenotyped HFpEF and non-HFpEF patients revealed that abnormal circulating BCAA levels were significantly associated with adverse outcomes.In the rodent model of HFpEF, significant impairment of BCAA catabolic activities in the heart and abnormal circulating BCAA levels were also observed.In ...