Department of Biological and Medical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic.
Centrum for Research and Development, University Hospital, Hradec Kralove, Czech Republic.
PLoS One. 2020 May 29;15(5):e0233725. doi: 10.1371/journal.pone.0233725. eCollection 2020.
Soluble endoglin (sEng) released into the circulation was suggested to be related to cardiovascular based pathologies. It was demonstrated that a combination of high sEng levels and long-term exposure (six months) to high fat diet (HFD) resulted in aggravation of endothelial dysfunction in the aorta. Thus, in this study, we hypothesized that a similar experimental design would affect the heart morphology, TGFβ signaling, inflammation, fibrosis, oxidative stress and eNOS signaling in myocardium in transgenic mice overexpressing human sEng. Three-month-old female transgenic mice overexpressing human sEng in plasma (Sol-Eng+ high) and their age-matched littermates with low levels of human sEng (Sol-Eng+ low) were fed a high-fat diet containing 1.25% of cholesterol and 40% of fat for six months. A blood analysis was performed, and the heart samples were analyzed by qRT-PCR and Western blot. The results of this study showed no effects of sEng and HFD on myocardial morphology/hypertrophy/fibrosis. However, the expression of pSmad2/3 and p-eNOS was reduced in Sol-Eng+ high mice. On the other hand, sEng and HFD did not significantly affect the expression of selected members of TGFβ signaling (membrane endoglin, TGFβRII, ALK-5, ALK-1, Id-1, PAI-1), inflammation (VCAM-1, ICAM-1), oxidative stress (NQO1, HO-1) and heart remodeling (PDGFβ, COL1A1, β-MHC). In conclusion, the results of this study confirmed that sEng, even combined with a high-fat diet inducing hypercholesterolemia administered for six months, does not affect the structure of the heart with respect to hypertrophy, fibrosis, inflammation and oxidative stress. Interestingly, pSmad2/3/p-eNOS signaling was reduced in both the heart in this study and the aorta in the previous study, suggesting a possible alteration of NO metabolism caused by six months exposure to high sEng levels and HFD. Thus, we might conclude that sEng combined with a high-fat diet might be related to the alteration of NO production due to altered pSmad2/3/p-eNOS signaling in the heart and aorta.
可溶性内皮糖蛋白（sEng）释放入循环系统被认为与心血管相关的病理学有关。研究表明，高 sEng 水平与长期（六个月）高脂肪饮食（HFD）暴露相结合会导致主动脉内皮功能障碍加重。因此，在这项研究中，我们假设类似的实验设计会影响过表达人 sEng 的转基因小鼠心脏形态、TGFβ 信号、炎症、纤维化、氧化应激和心肌 eNOS 信号。三个月大的雌性过表达人 sEng 的血浆转基因小鼠（Sol-Eng+高）及其年龄匹配的低水平人 sEng 的同窝小鼠（Sol-Eng+低）喂食含有 1.25%胆固醇和 40%脂肪的高脂肪饮食六个月。进行了血液分析，并通过 qRT-PCR 和 Western blot 分析了心脏样本。这项研究的结果表明，sEng 和 HFD 对心肌形态/肥大/纤维化没有影响。然而，Sol-Eng+高小鼠的 pSmad2/3 和 p-eNOS 表达减少。另一方面，sEng 和 HFD 对 TGFβ 信号的选定成员（膜内皮糖蛋白、TGFβRII、ALK-5、ALK-1、Id-1、PAI-1）、炎症（VCAM-1、ICAM-1）、氧化应激（NQO1、HO-1）和心脏重构（PDGFβ、COL1A1、β-MHC）的表达没有显著影响。总之，这项研究的结果证实，即使 sEng 与六个月高胆固醇饮食相结合，也不会影响心脏结构的肥大、纤维化、炎症和氧化应激。有趣的是，本研究中的心脏和先前研究中的主动脉中的 pSmad2/3/p-eNOS 信号均降低，这表明六个月暴露于高 sEng 水平和 HFD 可能导致 NO 代谢发生改变。因此，我们可以得出结论，sEng 与高脂肪饮食相结合可能与心脏和主动脉中因改变的 pSmad2/3/p-eNOS 信号导致的 NO 产生改变有关。
