Cunningham Mark W, Vaka Venkata Ramana, McMaster Kristen, Ibrahim Tarek, Cornelius Denise C, Amaral Lorena, Campbell Nathan, Wallukat Gerd, McDuffy Shyanne, Usry Nathan, Dechend Ralf, LaMarca Babbette
Depart. of Pharmacology & Toxicology, University of Mississippi Medical Center, Jackson, MS, United States.
Depart. of Emergency Medicine, University of Mississippi Medical Center, Jackson, MS, United States.
Pregnancy Hypertens. 2019 Jan;15:72-77. doi: 10.1016/j.preghy.2018.11.004. Epub 2018 Nov 30.
Women with preeclampsia (PE) have increased mean arterial pressure (MAP), natural killer (NK) cells, reactive oxygen species (ROS), and agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA). AT1-AA's administered to pregnant rodents produces a well-accepted model of PE. However, the role of NK cells and mitochondrial reactive oxygen species (mtROS) in AT1-AA mediated hypertension during pregnancy is unknown. We hypothesize that AT1-AA induced model of PE will exhibit elevated MAP, NK cells, and mtROS; while inhibition of the AT1-AA binding to the AT1R would be preventative. Pregnant rats were divided into 4 groups: normal pregnant (NP) (n = 5), NP + AT1-AA inhibitory peptide (NP +'n7AAc') (n = 3), NP + AT1-AA infused (NP + AT1-AA) (n = 10), and NP + AT1-AA +'n7AAc' (n = 8). Day 13, rats were surgically implanted with mini-pumps infusing either AT1-AA or AT1-AA +'n7AAc'. Day 19, tissue and blood was collected. MAP was elevated in AT1-AA vs. NP (119 ± 1 vs. 102 ± 2 mmHg, p < 0.05) and this was prevented by 'n7AAc' (108 ± 3). There was a 6 fold increase in renal activated NK cells in AT1-AA vs NP (1.2 ± 0.4 vs. 0.2 ± 0.1% Gated, p = 0.05) which returned to NP levels in AT1-AA +'n7AAc' (0.1 ± 0.1% Gated). Renal mtROS (317 ± 49 vs. 101 ± 13% Fold, p < 0.05) was elevated with AT1-AA vs NP and was decreased in AT1-AA +'n7AAc' (128 ± 16, p < 0.05). In conclusion, AT1-AA's increased MAP, NK cells, and mtROS which were attenuated by AT1-AA inhibition, thus highlighting new mechanisms of AT1-AA and the importance of drug therapy targeted to AT1-AAs in hypertensive pregnancies.
先兆子痫（PE）女性的平均动脉压（MAP）、自然杀伤（NK）细胞、活性氧（ROS）以及血管紧张素II 1型受体激动性自身抗体（AT1-AA）水平升高。给妊娠啮齿动物注射AT1-AA可产生一个广为接受的PE模型。然而，NK细胞和线粒体活性氧（mtROS）在妊娠期间AT1-AA介导的高血压中的作用尚不清楚。我们假设，AT1-AA诱导的PE模型将表现出MAP、NK细胞和mtROS升高；而抑制AT1-AA与AT1R的结合具有预防作用。将妊娠大鼠分为4组：正常妊娠（NP）组（n = 5）、NP + AT1-AA抑制肽（NP +'n7AAc'）组（n = 3）、NP + AT1-AA输注组（NP + AT1-AA）（n = 10）和NP + AT1-AA +'n7AAc'组（n = 8）。在第13天，通过手术给大鼠植入微量泵，输注AT1-AA或AT1-AA +'n7AAc'。在第19天，采集组织和血液。与NP组相比，AT1-AA组的MAP升高（119±1 vs. 102±2 mmHg，p < 0.05），而'n7AAc'可预防这种升高（108±3）。与NP组相比，AT1-AA组肾激活NK细胞增加了6倍（门控细胞为1.2±0.4 vs. 0.2±0.1%，p = 0.05），而在AT1-AA +'n7AAc'组中恢复到NP组水平（门控细胞为0.1±0.1%）。与NP组相比，AT1-AA组肾mtROS升高（317±49 vs. 101±13%倍，p < 0.05），而在AT1-AA +'n7AAc'组中降低（128±16，p < 0.05）。总之，AT1-AA可使MAP、NK细胞和mtROS升高，而AT1-AA抑制可使其减弱，从而突出了AT1-AA的新机制以及针对AT1-AA的药物治疗在高血压妊娠中的重要性。
