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.
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.
Circ Res. 2021 Jan 22;128(2):232-245. doi: 10.1161/CIRCRESAHA.120.317933. Epub 2020 Nov 12.
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.
This study was designed to investigate the metabolic mechanisms of HFpEF and test therapeutic interventions using a novel animal model.
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.
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.
超过 50%的心衰患者射血分数保留（HFpEF），而非射血分数降低。其病理生理学的复杂性和缺乏动物模型阻碍了 HFpEF 有效治疗方法的发展。
本研究旨在通过新型动物模型研究 HFpEF 的代谢机制并测试治疗干预措施。
通过在小鼠模型中结合年龄、长期高脂肪饮食和地塞米松棕榈酸酯挑战，我们能够重现 HFpEF 的多种特征。在这些小鼠中，线粒体过度乙酰化加剧，而增加酮体可用性则可挽救表型。HFpEF 小鼠由于过度组装 NLRP3 炎性体在过度乙酰化的线粒体上，导致 IL（白细胞介素）-1β/IL-18 过度产生和组织纤维化。增加 β-羟丁酸水平可减轻 NLRP3 炎性体的形成，并拮抗促炎细胞因子引发的线粒体功能障碍和纤维化。此外，β-羟丁酸可下调乙酰辅酶 A 池和线粒体乙酰化，部分通过激活 CS（柠檬酸合酶）和抑制脂肪酸摄取来实现。
因此，我们确定线粒体过度乙酰化和炎症的相互作用是 HFpEF 发病机制的关键驱动因素，通过促进 β-羟丁酸丰度可改善该机制。
