Endothelial sodium channel activation promotes cardiac stiffness and diastolic dysfunction in Western diet fed female mice.
Endothelial sodium channel activation promotes cardiac stiffness and diastolic dysfunction in Western diet fed female mice.
复制标题
DOI：
10.1016/j.metabol.2020.154223
复制
发表时间：
2020-08
期刊：
影响因子：
--
通讯作者：
Aroor AR
中科院分区：
文献类型：
--
作者：
Sowers JR;Habibi J;Jia G;Bostick B;Manrique-Acevedo C;Lastra G;Yang Y;Chen D;Sun Z;Domeier TL;Durante W;Whaley-Connell AT;Hill MA;Jaisser F;DeMarco VG;Aroor AR
肥胖与心肌纤维化和舒张舒张受损有关，这些异常在女性中尤为普遍。正常的冠状动脉内皮功能在调节舒张舒张中是不可或缺的，最近的研究表明内皮细胞（EC）矿化皮质激素受体（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的下游靶点，我们试图确定ec特异性缺失关键α亚基αEnNaC是否会阻止雌性小鼠饮食诱导的舒张舒张损伤。雌性αEnNaC KO小鼠和同窝对照组分别饲喂高脂肪（46%）、果葡糖浆（17.5%）和蔗糖（17.5%）的西式饲粮（WD） 12-16周。测定了原代培养的内皮细胞的体内心功能、体外心肌细胞硬度和EnNaC活性。另外的生化研究检查了心脏组织中氧化应激的指标，包括抗氧化Nrf2信号的各个方面。饲喂WD的雌性小鼠αEnNaC缺失显著减弱WD介导的舒张损伤。心脏舒张改善的同时，内皮细胞中nnac介导的Na+电流减少，心肌氧化应激减轻。此外，αEnNaC的缺失阻止了wd介导的离体心肌细胞僵硬度的增加。总的来说，这些发现支持了这样一种观点，即雌性小鼠WD喂养促进了血管中EnNaC的激活，导致心肌细胞僵硬和舒张功能障碍增加。
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. 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. 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. 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.
登录
查看更多内容
影响因子：
37.8
作者：
Shah SJ;Kitzman DW;Borlaug BA;van Heerebeek L;Zile MR;Kass DA;Paulus WJ
通讯作者：
Paulus WJ
影响因子：
13.8
作者：
Abraham NG;Junge JM;Drummond GS
通讯作者：
Drummond GS
影响因子：
39.3
作者：
Taqueti, Viviany R.;Solomon, Scott D.;Di Carli, Marcelo F.
通讯作者：
Di Carli, Marcelo F.
影响因子：
3.2
作者：
Durante W
通讯作者：
Durante W
影响因子：
--
作者：
Patel, Ravi B;Shah, Sanjiv J;Vaduganathan, Muthiah
通讯作者：
Vaduganathan, Muthiah