Trophoblastic mitochondrial DNA induces endothelial dysfunction and NLRP3 inflammasome activation: Implications for preeclampsia.

AIMS: Preeclampsia (PE) is characterised by systemic vascular endothelium dysfunction. Circulating trophoblastic secretions contribute to endothelial dysfunction, resulting in PE; however, the underlying mechanisms remain unclear. Herein, we aimed to determine the potential correlation between the release of trophoblastic mitochondrial deoxyribonucleic acid (DNA) (mtDNA) and endothelium damage in PE. MATERIALS AND METHODS: Umbilical cord sera and tissues from patients with PE were investigated for inflammasome activation. Following this, trophoblastic mitochondria were isolated from HTR-8/SVneo trophoblasts under 21 % oxygen (O2) or hypoxic conditions (1 % O2 for 48 h) for subsequent treatments. Primary human umbilical veinendothelial cells (HUVECs) were isolated from the human umbilical cord and then exposed to a vehicle (phosphate-buffered saline [PBS]), mtDNA, hypo-mtDNA, or hypo-mtDNA with INF39 (nucleotide oligomerisation domain-like receptor family pyrin domain containing 3 [NLRP3]-specific inhibitor) for 12 h before flow cytometry and immunoblotting. The effects of trophoblastic mtDNA on the endothelium were further analysed in vivo using enzyme-linked immunosorbent assay (ELISA) and vascular reactivity assay. The effects of mtDNA on vascular phenotypes were also tested on NLRP3 knockout mice. RESULTS: Elevated interleukin (IL)-1ß in PE sera was accompanied by NLRP3 inflammasome activation in cord tissues. In vitro and in vivo experiments revealed that the release of trophoblastic mtDNA could damage the endothelium via NLRP3 activation, resulting in the overexpression of NLRP3, caspase-1 p20, IL-1ß p17, and gasdermin D (GSDMD); reduced endothelial nitric oxide synthase (eNOS) levels; and impaired vascular relaxation. Flow cytometric analysis confirmed that extensive cell death was induced by mtDNA, and simultaneously, a more pronounced pro-apoptotic effect was caused by hypoxia-treated trophoblastic mtDNA. The NLRP3 knockout or pharmacologic NLRP3 inhibition partially reversed tumour necrosis factor-α (TNF-α) and IL-1ß levels and endothelium-dependent vasodilation in mice. CONCLUSION: These findings demonstrate that trophoblastic mtDNA induced NLRP3/caspase-1/IL-1ß signalling activation, eNOS-related endothelial injury, and vasodilation dysfunction in PE.

[Genetic characteristics of wheat functional leaves at filling stage under different water regimes].

Taking one hundred and fifty doubled haploid (DH) lines of winter wheat cultivars Hanxuan 10 x Lumai 14 as well as their parents as test materials, the genetic bases of top three leaves length, breadth, and angle at mid-filling stage, and their correlations with yield traits were studied under two water regimes rainfed (drought stress, DS) and well-irrigation (WI) in 2005-2007. Under DS, the leaf length and width of DH lines and their parents were significantly lower than those under WI, whereas the leaf angle had a miscellaneous variation. Under the two water regimes, all the test traits of DH lines had a transgressive segregation, with the variation coefficients ranged from 5.1% to 45.9%. The heritability and gene numbers for the given traits showed great differences. Under WI and DS, the heritability of flag leaf angle (FLA) was the highest (91% and 97%, respectively), and that of the third leaf angle (TLA) was the lowest (23% and 31%, respectively). However, the gene number for FLA (4 and 2 under WI and DS, respectively) was the least, and that of TLA (21 and 25, respectively) in 2007 was the most. Interactive effects were observed among the genes controlling FLA, second leaf angle (SLA), and TLA under WI and DS, and controlling third leaf length (TLL) under WI. The grain number per spike and the grain weight per spike were positively correlated with the length and width of top three leaves, and the thousand-grain weight and the yield per plant were significantly correlated with TLL, FLA, and SLA, but all correlation coefficients were smaller ( < 0.481). It was suggested that the selection of top three leaves length and width should be carried out in the early generations of breeding procedure, while that of leaf angles should be carried out in advanced generations. An appropriate soil moisture regime retained in the critical growth period of the leaves would promote their growth and contribute to the grain yield.