Lamothe Jeremy, Khurana Sandhya, Tharmalingam Sujeenthar, Williamson Chad, Byrne Collin J, Lees Simon J, Khaper Neelam, Kumar Aseem, Tai T C
Biomolecular Sciences, Laurentian University, Sudbury, ON P3E 2C6, Canada.
Medical Science Division, Northern Ontario School of Medicine, Sudbury, ON P3E 2C6, Canada.
Antioxidants (Basel). 2021 Mar 29;10(4):531. doi: 10.3390/antiox10040531.
The field of cardiovascular fetal programming has emphasized the importance of the uterine environment on postnatal cardiovascular health. Studies have linked increased fetal glucocorticoid exposure, either from exogenous sources (such as dexamethasone (Dex) injections), or from maternal stress, to the development of adult cardiovascular pathologies. Although the mechanisms are not fully understood, alterations in gene expression driven by altered oxidative stress and epigenetic pathways are implicated in glucocorticoid-mediated cardiovascular programming. Antioxidants, such as the naturally occurring polyphenol epigallocatechin gallate (EGCG), or the superoxide dismutase (SOD) 4-hydroxy-TEMPO (TEMPOL), have shown promise in the prevention of cardiovascular dysfunction and programming. This study investigated maternal antioxidant administration with EGCG or TEMPOL and their ability to attenuate the fetal programming of hypertension via Dex injections in WKY rats. Results from this study indicate that, while Dex-programming increased blood pressure in male and female adult offspring, administration of EGCG or TEMPOL via maternal drinking water attenuated Dex-programmed increases in blood pressure, as well as changes in adrenal mRNA and protein levels of catecholamine biosynthetic enzymes phenylalanine hydroxylase (), tyrosine hydroxylase (), dopamine beta hydroxylase (), and phenylethanolamine N-methyltransferase (), in a sex-specific manner. Furthermore, programmed male offspring displayed reduced antioxidant glutathione peroxidase 1 () expression, increased superoxide dismutase 1 () and catalase () expression, and increased pro-oxidant NADPH oxidase activator 1 (Noxa1) expression in the adrenal glands. In addition, prenatal Dex exposure alters expression of epigenetic regulators histone deacetylase () 1, 5, 6, 7, 11, in male and in female offspring. These results suggest that glucocorticoids may mediate the fetal programming of hypertension via alteration of epigenetic machinery and oxidative stress pathways.
心血管胎儿编程领域强调了子宫环境对出生后心血管健康的重要性。研究已将胎儿糖皮质激素暴露增加（无论是来自外源（如地塞米松（Dex）注射）还是母体应激）与成人心血管疾病的发生联系起来。尽管其机制尚未完全了解，但由氧化应激和表观遗传途径改变驱动的基因表达变化与糖皮质激素介导的心血管编程有关。抗氧化剂，如天然存在的多酚表没食子儿茶素没食子酸酯（EGCG）或超氧化物歧化酶（SOD）4-羟基-TEMPO（TEMPOL），已显示出预防心血管功能障碍和编程的前景。本研究调查了母体给予EGCG或TEMPOL抗氧化剂及其通过在WKY大鼠中注射Dex减轻高血压胎儿编程的能力。本研究结果表明，虽然Dex编程增加了成年雄性和雌性后代的血压，但通过母体饮用水给予EGCG或TEMPOL可减轻Dex编程引起的血压升高，以及肾上腺中儿茶酚胺生物合成酶苯丙氨酸羟化酶（）、酪氨酸羟化酶（）、多巴胺β羟化酶（）和苯乙醇胺N-甲基转移酶（）的mRNA和蛋白质水平变化，且具有性别特异性。此外，编程的雄性后代肾上腺中抗氧化剂谷胱甘肽过氧化物酶1（）的表达降低，超氧化物歧化酶1（）和过氧化氢酶（）的表达增加，促氧化剂NADPH氧化酶激活剂1（Noxa1）的表达增加。此外，产前Dex暴露会改变雄性和雌性后代中表观遗传调节因子组蛋白脱乙酰酶（）1、5、6、7、11的表达。这些结果表明，糖皮质激素可能通过表观遗传机制和氧化应激途径的改变介导高血压的胎儿编程。
