Targeting Mitochondria-Inflammation Circuit by β-Hydroxybutyrate Mitigates HFpEF
Targeting Mitochondria-Inflammation Circuit by β-Hydroxybutyrate Mitigates HFpEF
复制标题
通过 β-羟基丁酸靶向线粒体炎症回路可缓解 HFpEF
DOI：
10.1161/circresaha.120.317933
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发表时间：
2021-01-22
影响因子：
20.1
通讯作者：
Li, Tao
中科院分区：
文献类型：
--
作者：
Deng, Yan;Xie, Maodi;Li, Tao
补充数字内容可在正文中找到。理论基础：超过50%的心力衰竭患者保留了射血分数(HFpEF)，而不是减少了射血分数。其复杂的病理生理机制和缺乏动物模型阻碍了HFpEF有效治疗的发展。目的：通过建立一种新的动物模型，研究HFpEF的代谢机制，并探讨其治疗干预措施。方法和结果：通过在小鼠模型中结合年龄、长期高脂饮食和脱氧皮质酮激发，我们能够重新获得HFpEF的各种特征。在这些小鼠中，线粒体的超乙酰化加剧，同时增加了酮体的利用率，挽救了表型。高脂血症小鼠表现出IL(IL)-1β/IL-18的过度产生和组织纤维化，这是由于NLPR3炎性小体在高乙酰化的线粒体上组装增加所致。增加β-羟丁酸水平可减少NLPR3炎性小体的形成，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-羟丁酸酯下调乙酰辅酶A池和线粒体乙酰化，部分是通过激活CS(柠檬酸合成酶)和抑制脂肪酸摄取。结论：因此，我们认为线粒体超乙酰化和炎症的相互作用是高压性充血性心力衰竭发病的关键驱动因素，这种影响可以通过增加β-羟丁酸的丰度来改善。
Supplemental Digital Content is available in the text. 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.