Objective

Obesity is associated with myocardial fibrosis and impaired diastolic relaxation, abnormalities that are especially prevalent in women. Normal coronary vascular endothelial function is integral in mediating diastolic relaxation, and recent work suggests increased activation of the endothelial cell (EC) mineralocorticoid receptor (ECMR) is associated with impaired diastolic relaxation. As the endothelial Na⁺ channel (EnNaC) is a downstream target of the ECMR, we sought to determine whether EC-specific deletion of the critical alpha subunit, αEnNaC, would prevent diet induced-impairment of diastolic relaxation in female mice.

Methods and materials

Female αEnNaC KO mice and littermate controls were fed a Western diet (WD) high in fat (46%), fructose corn syrup (17.5%) and sucrose (17.5%) for 12–16 weeks. Measurements were conducted for in vivo cardiac function, in vitro cardiomyocyte stiffness and EnNaC activity in primary cultured ECs. Additional biochemical studies examined indicators of oxidative stress, including aspects of antioxidant Nrf2 signaling, in cardiac tissue.

Results

Deletion of αEnNaC in female mice fed a WD significantly attenuated WD mediated impairment in diastolic relaxation. Improved cardiac relaxation was accompanied by decreased EnNaC-mediated Na⁺ currents in ECs and reduced myocardial oxidative stress. Further, deletion of αEnNaC prevented WD-mediated increases in isolated cardiomyocyte stiffness.

Conclusion

Collectively, these findings support the notion that WD feeding in female mice promotes activation of EnNaC in the vasculature leading to increased cardiomyocyte stiffness and diastolic dysfunction.

中文翻译：

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内皮钠通道激活促进西方饮食喂养的雌性小鼠的心脏僵硬和舒张功能障碍。

客观的

肥胖与心肌纤维化和舒张松弛受损有关，这些异常在女性中尤为普遍。正常的冠状血管内皮功能是调节舒张舒张不可或缺的一部分，最近的研究表明，内皮细胞 (EC) 盐皮质激素受体 (ECMR) 的激活增加与舒张舒张受损有关。由于内皮 Na ⁺通道 (EnNaC) 是 ECMR 的下游靶标，我们试图确定关键 α 亚基 αEnNaC 的 EC 特异性缺失是否会防止饮食诱导的雌性小鼠舒张舒张松弛受损。

方法和材料

雌性 αEnNaC KO 小鼠和同窝对照小鼠被喂食高脂肪 (46%)、果糖玉米糖浆 (17.5%) 和蔗糖 (17.5%) 的西方饮食 (WD) 12-16 周。对原代培养的 ECs 中的体内心脏功能、体外心肌细胞硬度和 EnNaC 活性进行了测量。其他生化研究检查了心脏组织中氧化应激的指标，包括抗氧化剂 Nrf2 信号传导的各个方面。

结果

在喂食 WD 的雌性小鼠中删除 αEnNaC 可显着减轻 WD 介导的舒张舒张损伤。心脏舒张的改善伴随着ECs 中EnNaC 介导的 Na ⁺电流的降低和心肌氧化应激的降低。此外，αEnNaC 的缺失阻止了 WD 介导的离体心肌细胞硬度增加。

结论

总的来说，这些发现支持这样的观点，即雌性小鼠喂食 WD 会促进血管系统中 EnNaC 的激活，从而导致心肌细胞僵硬和舒张功能障碍。