State Key Laboratory for Innovation and Transformation of Luobing Theory, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
Department of Cardiology, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
J Nutr. 2024 Oct;154(10):3031-3041. doi: 10.1016/j.tjnut.2024.08.006. Epub 2024 Aug 14.
There is an urgent need to develop an efficient therapeutic strategy for heart failure with preserved ejection fraction (HFpEF), which is mediated by phenotypic changes in cardiac macrophages. We previously reported that vitamin B-6 inhibits macrophage-mediated inflammasome activation.
We sought to examine whether the prophylactic use of vitamin B-6 prevents HFpEF.
HFpEF model was elicited by a combination of high-fat diet and N-nitro-l-arginine methyl ester supplement in mice. Cardiac function was assessed using conventional echocardiography and Doppler imaging. Immunohistochemistry and immunoblotting were used to detect changes in the macrophage phenotype and myocardial remodeling-related molecules.
Co-administration of vitamin B-6 with HFpEF mice mitigated HFpEF phenotypes, including diastolic dysfunction, cardiac macrophage phenotypic shifts, fibrosis, and hypertrophy. Echocardiographic improvements were observed, with the E/E' ratio decreasing from 42.0 to 21.6 and the E/A ratio improving from 2.13 to 1.17. The exercise capacity also increased from 295.3 to 657.7 min. However, these beneficial effects were negated in downstream of kinase (DOK) 3-deficient mice. Mechanistically, vitamin B-6 increased DOK3 protein concentrations and inhibited macrophage phenotypic changes, which were abrogated by an AMP-activated protein kinase inhibitor.
Vitamin B-6 increases DOK3 signaling to lower risk of HFpEF by inhibiting phenotypic changes in cardiac macrophages.
目前迫切需要开发一种有效的治疗射血分数保留型心力衰竭（HFpEF）的策略，这种策略是由心脏巨噬细胞表型变化介导的。我们之前报道过，维生素 B-6 可抑制巨噬细胞介导的炎症小体激活。
我们试图研究预防性使用维生素 B-6 是否可以预防 HFpEF。
通过高脂肪饮食和 N-硝基-L-精氨酸甲酯补充剂联合作用在小鼠中建立 HFpEF 模型。使用常规超声心动图和多普勒成像评估心功能。免疫组织化学和免疫印迹用于检测巨噬细胞表型和心肌重构相关分子的变化。
维生素 B-6 与 HFpEF 小鼠共同给药可减轻 HFpEF 表型，包括舒张功能障碍、心脏巨噬细胞表型转变、纤维化和肥大。观察到超声心动图改善，E/E' 比值从 42.0 降至 21.6，E/A 比值从 2.13 改善至 1.17。运动能力也从 295.3 增加到 657.7 分钟。然而，这些有益作用在激酶（DOK）3 缺陷型小鼠中被否定。机制上，维生素 B-6 增加了 DOK3 蛋白浓度并抑制了巨噬细胞表型变化，而 AMP 激活的蛋白激酶抑制剂则消除了这种作用。
维生素 B-6 通过抑制心脏巨噬细胞的表型变化来增加 DOK3 信号，从而降低 HFpEF 的风险。
