Targeting Mitochondria-Inflammation Circuit by β-Hydroxybutyrate Mitigates HFpEF.

Abstract

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)-1β/IL-18 and tissue fibrosis due to increased assembly of NLPR3 inflammasome on hyperacetylated mitochondria. Increasing β-hydroxybutyrate level attenuated NLPR3 inflammasome formation and antagonized proinflammatory cytokine-triggered mitochondrial dysfunction and fibrosis. Moreover, β-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 β-hydroxybutyrate abundance.

• Authors: Yan Deng, Maodi Xie, Qian Li, Xuewen Xu, Wei Ou, Yabing Zhang, Haitao Xiao, Hai Yu, Yanyi Zheng, Yu Liang, Chunling Jiang, Guo Chen, Dan Du, Wen Zheng, Shisheng Wang, Meng Gong, Yaohui Chen, Rong Tian, Tao Li
• Journal: Circulation research (Circ Res) Vol. 128 Issue 2 Pg. 232-245 (01 22 2021) ISSN: 1524-4571 [Electronic] United States
• PMID: 33176578 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• Fatty Acids
• Inflammation Mediators
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Sirt3 protein, mouse
• Acetyl Coenzyme A
• Sirtuin 3
• 3-Hydroxybutyric Acid

Topics

• 3-Hydroxybutyric Acid
• 3T3 Cells
• Acetyl Coenzyme A (metabolism)
• Acetylation
• Aged
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Cytokines (metabolism)
• Disease Models, Animal
• Energy Metabolism (drug effects)
• Fatty Acids (metabolism)
• Female
• Fibrosis
• Heart Failure (drug therapy, metabolism, pathology, physiopathology)
• Humans
• Inflammation (drug therapy, metabolism, pathology, physiopathology)
• Inflammation Mediators (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Mitochondria, Heart (drug effects, metabolism, pathology)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• RAW 264.7 Cells
• Rats
• Sirtuin 3 (genetics, metabolism)
• Stroke Volume (drug effects)
• Ventricular Function, Left (drug effects)