Guo Jun, Shi Yajun, Yu Xi, Zhao Yan, Wei Bin, Huo Ming, Lu Likui, Li Lingjun, Gao Qinqin, Sun Miao
Institute for Fetology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China.
Dushu Lake Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China.
Hypertens Res. 2025 Mar;48(3):1080-1098. doi: 10.1038/s41440-024-02023-9. Epub 2024 Dec 6.
Many epidemiologic and animal studies have shown that maternal hypothyroidism is associated with an increased risk of hypertension in offspring in later life. In this study, we established a maternal hypothyroidism rat model to explore the underlying mechanism that contributes to elevated blood pressure in adult male offspring of hypothyroid mothers. The levels of thyroid hormones (THs) in the offspring were measured using ELISA kits. Blood pressure (BP) and depressor response were recorded in conscious, freely moving rats. Vascular reactivity was conducted in isolated mesenteric arteries (MAs) using a myograph. We used real-time quantitative PCR (RT-qPCR) and Western blots to examine the mRNA and protein expression of relevant molecules in MAs. The A7r5 cells were transfected with small interfering RNA (siRNA) to further investigate the gene functions. The following findings were observed: Basal systolic BP and diastolic BP was significantly increased, accompanied by attenuated depressor response and decreased vascular sensitivity to sodium nitroprusside (SNP). Reactive Oxygen Species (ROS) levels in the MAs were enhanced, along with decreased expression of the THRA1/PGC-1α/SIRT3 pathway. In A7r5 cells, triiodothyronine (T3) pretreatment improved the PGC-1α/SIRT3 pathway and reduced ROS levels after HO-induced oxidative stress. In contrast, the knockdown of THRA1 or SIRT3 diminished the above effects of T3. Down-regulation of THRA1 contributed to a decline in the PGC-1α/SIRT3 pathway, which causes an increased production of ROS. This indicates that the T3-THRA1/PGC-1α/SIRT3 pathway plays a protective role in the regulation of BP and may be a potential therapeutic strategy against hypertension.
许多流行病学和动物研究表明，母亲甲状腺功能减退与后代成年后患高血压的风险增加有关。在本研究中，我们建立了母亲甲状腺功能减退大鼠模型，以探讨导致甲状腺功能减退母亲成年雄性后代血压升高的潜在机制。使用酶联免疫吸附测定试剂盒测量后代甲状腺激素（THs）水平。在清醒、自由活动的大鼠中记录血压（BP）和降压反应。使用肌张力测定仪在离体肠系膜动脉（MAs）中进行血管反应性检测。我们使用实时定量聚合酶链反应（RT-qPCR）和蛋白质免疫印迹法检测MAs中相关分子的mRNA和蛋白质表达。用小干扰RNA（siRNA）转染A7r5细胞以进一步研究基因功能。观察到以下结果：基础收缩压和舒张压显著升高，同时降压反应减弱，血管对硝普钠（SNP）的敏感性降低。MAs中的活性氧（ROS）水平升高，同时THRA1/PGC-1α/SIRT3通路的表达降低。在A7r5细胞中，三碘甲状腺原氨酸（T3）预处理改善了PGC-1α/SIRT3通路，并在过氧化氢诱导的氧化应激后降低了ROS水平。相反，敲低THRA1或SIRT3可减弱T3的上述作用。THRA1的下调导致PGC-1α/SIRT3通路下降，从而导致ROS产生增加。这表明T3-THRA1/PGC-1α/SIRT3通路在血压调节中起保护作用，可能是抗高血压的潜在治疗策略。
