Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York
Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, New York.
J Pharmacol Exp Ther. 2019 Oct;371(1):88-94. doi: 10.1124/jpet.119.260471. Epub 2019 Jul 12.
Vascular dysfunction associated with hypertension comprises hypercontractility and impaired vasodilation. We have previously demonstrated that triiodothyronine (T3), the active form of thyroid hormone, has vasodilatory effects acting through rapid onset mechanisms. In the present study, we examined whether T3 mitigates vascular dysfunction associated with hypertension. To test the direct effects of T3 in hypertensive vessels, aortas from female Dahl salt-sensitive (Dahl SS) rats fed a high-salt diet (8% NaCl, HS group) and their age-matched controls fed a standard low-salt diet (0.3% NaCl, LS group) for 16 weeks were isolated and used in ex vivo vascular reactivity studies. We confirmed that the HS group exhibited a higher systolic blood pressure in comparison with the control LS group and displayed aortic remodeling. Aortas from both groups were pretreated with T3 (0.1 M) for 30 minutes at 37°C in a 5% CO incubator before functional vascular studies. T3 treatment significantly attenuated hypercontractility and improved impaired endothelium-dependent vasodilation in aortas from the HS group. These vascular improvements in response to T3 were accompanied by increased phosphorylation of vasodilator-stimulated phosphoprotein (VASP) at serine 239, a vasodilatory factor of the cGMP-dependent protein kinase (PKG)/VASP signaling pathway in vascular smooth muscle cells. Moreover, increased production of reactive oxygen species in aortas from the HS group were significantly reduced by T3, suggesting a potential antioxidant effect of T3 in the vasculature. These results demonstrate that T3 can mitigate hypertension-related vascular dysfunction through the VASP signaling pathway and by reducing vascular ROS production. SIGNIFICANCE STATEMENT: This study demonstrates that triiodothyronine (T3) directly acts on vascular tone and has a beneficial effect in hypertension-induced vascular dysfunction. T3 augmented vasodilation and diminished vasoconstriction in blood vessels from hypertensive rats in association with activation of the protein kinase G/vasodilator-stimulated phosphoprotein signaling pathway that activates vascular relaxation and exerted an antioxidant effect. Collectively, these results show that T3 is a potential vasoprotective agent with rapid action on hypertension-related vascular dysfunction.
与高血压相关的血管功能障碍包括高收缩性和血管舒张受损。我们之前已经证明，三碘甲状腺原氨酸（T3），甲状腺激素的活性形式，具有通过快速起始机制发挥的血管舒张作用。在本研究中，我们研究了 T3 是否可以减轻与高血压相关的血管功能障碍。为了测试 T3 在高血压血管中的直接作用，将喂食高盐饮食（8% NaCl，HS 组）的雌性 Dahl 盐敏感（Dahl SS）大鼠的主动脉和它们年龄匹配的喂食标准低盐饮食（0.3% NaCl，LS 组）16 周的主动脉分离出来，并用于离体血管反应性研究。我们证实 HS 组的收缩压明显高于对照组 LS 组，并表现出主动脉重塑。将来自两组的主动脉在 37°C 的 5% CO 孵育箱中用 T3（0.1 M）预处理 30 分钟，然后进行功能血管研究。T3 处理显著减轻了 HS 组主动脉的高收缩性，并改善了受损的内皮依赖性血管舒张。T3 对血管的这些改善伴随着血管平滑肌细胞中环磷酸鸟苷依赖性蛋白激酶（PKG）/VASP 信号通路的血管舒张因子血管扩张刺激磷蛋白（VASP）丝氨酸 239 的磷酸化增加。此外，HS 组主动脉中活性氧的产生显著减少，这表明 T3 在血管中具有潜在的抗氧化作用。这些结果表明，T3 可以通过 VASP 信号通路和减少血管 ROS 产生来减轻高血压相关的血管功能障碍。意义陈述：本研究表明，三碘甲状腺原氨酸（T3）可直接作用于血管张力，对高血压引起的血管功能障碍具有有益作用。T3 增强了高血压大鼠血管的血管舒张作用，并减弱了血管收缩作用，与激活血管松弛的蛋白激酶 G/血管扩张刺激磷蛋白信号通路有关，并发挥了抗氧化作用。总的来说，这些结果表明，T3 是一种潜在的血管保护剂，对高血压相关的血管功能障碍具有快速作用。
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