期刊
CIRCULATION RESEARCH
卷 128, 期 2, 页码 232-245出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.120.317933
关键词
fibrosis; heart failure; inflammasomes; inflammation; mitochondria
资金
- National Natural Science Foundation of China [81970715, 81770815, 81772079, 81873500, 81971806]
- National Key Research and Development Program of China [2018YFC1106502]
- 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University [ZYGD18014]
- Innovation Spark Project of Sichuan University [2018SCUH0065]
- Key Research and Development Program of Sichuan Province [2019YFS0222, 2019YFS0252]
This study identified the interplay of mitochondrial hyperacetylation and inflammation as a key driver in HFpEF pathogenesis, and showed that increasing beta-hydroxybutyrate levels can ameliorate the disease by reducing inflammation and mitochondrial dysfunction.
Rationale: Over 50% of patients with heart failure have preserved ejection fraction (HFpEF), rather than reduced ejection fraction. Complexity of its pathophysiology and the lack of animal models hamper the development of effective therapy for HFpEF. Objective: This study was designed to investigate the metabolic mechanisms of HFpEF and test therapeutic interventions using a novel animal model. Methods and Results: By combining the age, long-term high-fat diet, and desoxycorticosterone pivalate challenge in a mouse model, we were able to recapture the myriad features of HFpEF. In these mice, mitochondrial hyperacetylation exacerbated while increasing ketone body availability rescued the phenotypes. The HFpEF mice exhibited overproduction of IL (interleukin)-1 beta/IL-18 and tissue fibrosis due to increased assembly of NLPR3 inflammasome on hyperacetylated mitochondria. Increasing beta-hydroxybutyrate level attenuated NLPR3 inflammasome formation and antagonized proinflammatory cytokine-triggered mitochondrial dysfunction and fibrosis. Moreover, beta-hydroxybutyrate downregulated the acetyl-CoA pool and mitochondrial acetylation, partially via activation of CS (citrate synthase) and inhibition of fatty acid uptake. Conclusions: Therefore, we identify the interplay of mitochondrial hyperacetylation and inflammation as a key driver in HFpEF pathogenesis, which can be ameliorated by promoting beta-hydroxybutyrate abundance.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据