From the Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (M.E.M., Q.L., S.L.I., I.Z.J.).
Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA (M.E.M., I.Z.J.).
Arterioscler Thromb Vasc Biol. 2019 Aug;39(8):1588-1601. doi: 10.1161/ATVBAHA.119.312954. Epub 2019 Jul 11.
MR (mineralocorticoid receptor) activation is associated with cardiovascular ischemia in humans. This study explores the role of the MR in atherosclerotic mice of both sexes and identifies a sex-specific role for endothelial cell (EC)-MR in vascular inflammation. Approach and Results: In the AAV-PCSK9 (adeno-associated virus-proprotein convertase subtilisin/kexin type 9) mouse atherosclerosis model, MR inhibition attenuated vascular inflammation in males but not females. Further studies comparing male and female littermates with intact MR or EC-MR deletion revealed that although EC-MR deletion did not affect plaque size in either sex, it reduced aortic arch inflammation specifically in male mice as measured by flow cytometry. Moreover, MR-intact females had larger plaques but were protected from vascular inflammation compared with males. Intravital microscopy of the mesenteric vasculature demonstrated that EC-MR deletion attenuated TNFα (tumor necrosis factor α)-induced leukocyte slow rolling and adhesion in males, while females exhibited fewer leukocyte-endothelial interactions with no additional effect of EC-MR deletion. These effects corresponded with decreased TNFα-induced expression of the endothelial adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and E-selectin in males with EC-MR deletion compared with MR-intact males and females of both genotypes. These observations were also consistent with MR and estrogen regulation of ICAM-1 transcription and E-selectin expression in primary cultured mouse ECs and human umbilical vein ECs.
In male mice, EC-MR deletion attenuates leukocyte-endothelial interactions, plaque inflammation, and expression of E-selectin and ICAM-1, providing a potential mechanism by which the MR promotes vascular inflammation. In females, plaque inflammation and leukocyte-endothelial interactions are decreased relative to males and EC-MR deletion is not protective.
MR（盐皮质激素受体）的激活与人类心血管缺血有关。本研究探讨了 MR 在雄性和雌性动脉粥样硬化小鼠中的作用，并确定了内皮细胞（EC）-MR 在血管炎症中的性别特异性作用。
在 AAV-PCSK9（腺相关病毒-前蛋白转化酶枯草溶菌素/糜蛋白酶 9）小鼠动脉粥样硬化模型中，MR 抑制减弱了雄性小鼠的血管炎症，但对雌性小鼠没有影响。进一步比较雄性和雌性同窝仔鼠的完整 MR 或 EC-MR 缺失，发现尽管 EC-MR 缺失对两性斑块大小均无影响，但通过流式细胞术检测，其特异性地减少了雄性小鼠主动脉弓炎症。此外，MR 完整的雌性小鼠斑块较大，但与雄性相比，其血管炎症受到保护。肠系膜血管的活体显微镜检查显示，EC-MR 缺失减弱了 TNFα（肿瘤坏死因子α）诱导的雄性白细胞缓慢滚动和黏附，而雌性的白细胞-内皮相互作用较少，EC-MR 缺失无额外影响。这些作用与 EC-MR 缺失的雄性小鼠中 TNFα 诱导的内皮黏附分子 ICAM-1（细胞间黏附分子-1）和 E-选择素表达减少相对应，与 MR 完整的雄性和雌性同窝仔鼠相比。这些观察结果也与 MR 和雌激素对原代培养的小鼠 EC 和人脐静脉 EC 中 ICAM-1 转录和 E-选择素表达的调节一致。
在雄性小鼠中，EC-MR 缺失减弱了白细胞-内皮相互作用、斑块炎症以及 E-选择素和 ICAM-1 的表达，为 MR 促进血管炎症提供了潜在机制。在雌性小鼠中，与雄性相比，斑块炎症和白细胞-内皮相互作用减少，而 EC-MR 缺失没有保护作用。
