Kluknavsky Michal, Micurova Andrea, Cebova Martina, Şaman Ezgi, Cacanyiova Sona, Bernatova Iveta
Centre of Experimental Medicine, Slovak Academy of Sciences, Institute of Normal and Pathological Physiology, 841 04 Bratislava, Slovakia.
Antioxidants (Basel). 2022 Dec 1;11(12):2385. doi: 10.3390/antiox11122385.
Reduced angiotensin 1-7 bioavailability due to inhibition of angiotensin-converting enzyme 2 (ACE2) may contribute to increased mortality in hypertensive individuals during COVID-19. However, effects of ACE2 inhibitor MLN-4760 in brain functions remain unknown. We investigated the selected behavioural and hemodynamic parameters in spontaneously hypertensive rats (SHRs) after a 2-week s.c. infusion of MLN-4760 (dose 1 mg/kg/day). The biochemical and molecular effects of MLN-4760 were investigated in the brainstem and blood plasma. MLN-4760 had no effects on hemodynamic and behavioural parameters. However, MLN-4760 increased plasma hydrogen sulfide (HS) level and total nitric oxide (NO) synthase activity and conjugated dienes in the brainstem. Increased NO synthase activity correlated positively with gene expression of while plasma HS levels correlated positively with gene expressions of HS-producing enzymes , and . MLN-4760 administration increased gene expression of , , , and , which positively correlated with expression of gene encoding the redox-sensitive transcription factor NRF2. Collectively, MLN-4760 did not exacerbate pre-existing hypertension and behavioural hyperactivity/anxiety in SHRs. However, MLN-4760-induced oxidative damage in brainstem was associated with activation of NO- and HS-mediated compensatory mechanisms and with increased gene expression of antioxidant, NO- and HS-producing enzymes that all correlated positively with elevated expression.
由于血管紧张素转换酶2（ACE2）受到抑制，血管紧张素1-7的生物利用度降低，这可能导致高血压个体在感染新型冠状病毒肺炎期间死亡率增加。然而，ACE2抑制剂MLN-4760对脑功能的影响尚不清楚。我们研究了在皮下注射MLN-4760（剂量为1毫克/千克/天）2周后，自发性高血压大鼠（SHRs）的选定行为和血流动力学参数。在脑干和血浆中研究了MLN-4760的生化和分子效应。MLN-4760对血流动力学和行为参数没有影响。然而，MLN-4760增加了血浆硫化氢（HS）水平、总一氧化氮（NO）合酶活性以及脑干中的共轭二烯。一氧化氮合酶活性增加与[具体基因名称未给出]的基因表达呈正相关，而血浆HS水平与产HS酶[具体酶名称未给出]、[具体酶名称未给出]和[具体酶名称未给出]的基因表达呈正相关。给予MLN-4760增加了[具体基因名称未给出]、[具体基因名称未给出]、[具体基因名称未给出]、[具体基因名称未给出]和[具体基因名称未给出]的基因表达，这些与编码氧化还原敏感转录因子NRF2的[具体基因名称未给出]基因的表达呈正相关。总体而言，MLN-4760并未加重SHRs预先存在的高血压和行为多动/焦虑。然而，MLN-4760诱导的脑干氧化损伤与NO和HS介导的代偿机制激活以及抗氧化、产NO和产HS酶的基因表达增加有关，所有这些都与升高的[具体基因名称未给出]表达呈正相关。
