Yan Deng1,2, Maodi Xie1,2, Qian Li1,2, Xuewen Xu3, Wei Ou1, Yabing Zhang1,2, Haitao Xiao3, Hai Yu1,2, Yanyi Zheng1,2, Yu Liang1,2, Chunling Jiang1,2, Guo Chen1,2, Dan Du1, Wen Zheng1, Shisheng Wang1, Meng Gong1, Yaohui Chen4, Rong Tian5, Tao Li1,2. 1. Laboratory of Mitochondrial and Metabolism, Department of Anesthesiology, National Clinical Research Center for Geriatrics (Y.D., M.X., Q.L., W.O., Y. Zhang, H.Y., Y. Zheng, Y.L., C.J., G.C., D.D., W.Z., S.W., M.G., T.L.), West China Hospital of Sichuan University, Chengdu. 2. Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Center (Y.D., M.X., Q.L., W.O., Y. Zhang, H.Y., Y. Zheng, Y.L., C.J., G.C., T.L.), West China Hospital of Sichuan University, Chengdu. 3. Department of Burn and Plastic Surgery (X.X., H.X.), West China Hospital of Sichuan University, Chengdu. 4. Chest Oncology Institute (Y.C.), West China Hospital of Sichuan University, Chengdu. 5. Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, University of Washington, Seattle (R.T.).
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.
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: Kim L Ho; Qutuba G Karwi; David Connolly; Simran Pherwani; Ezra B Ketema; John R Ussher; Gary D Lopaschuk Journal: Diabetologia Date: 2022-01-07 Impact factor: 10.122