THRA1/PGC-1α/SIRT3 pathway regulates oxidative stress and is implicated in hypertension of maternal hypothyroid rat offspring.

Abstract

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 H2O2-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.