Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05
  • 2024-06
  • 2024-07
  • 2024-08
  • 2024-09
  • 2024-10

    • We demonstrated clearly that the overexpression of

    2024-01-03

    We demonstrated clearly that the overexpression of sFlt-1 significantly increased arginase GDC-0349 and enhanced arginase activity in HUVECs (Fig. 3). NO formation is related inversely to serum levels of sFlt-1 in preeclampsia [11]. The disorder of NO formation, which was involved in hypertension and proteinuria in preeclampsia, was induced by impaired NOS activity. The endothelial dysfunction could result from sFlt-1-induced antagonism of VEGF [2]. However, our results suggested that overexpression of sFlt-1 directly led to higher arginase expression and activity in HUVECs. A previous report stated that when either arginase or NOS is activated, it competitively inhibits the action of the other, both by direct utilization of increased amounts of l-arginine and by secondary means [20] [21]. Thus far, our data suggested that higher arginase expression and activity induced by overexpression of sFlt-1 impaired NOS activity, which leads to NO formation disorder. Our data indicated that increased sFlt-1 could not regulate arginase, resulting in abnormal NO synthase associated with a preeclamptic phenotype. Together with previous reports, our results explain the mechanism between sFlt-1, arginase, and NO. Finally, we examined the effect on sFlt-1 by inhibiting arginase. Our data showed that BEC, an arginase inhibitor, impaired sFlt-1 expression in HUVECs (Fig. 2D). This result strongly supported the mechanism that sFlt-1 itself was likely to maintain angiogenic/anti-angiogenic homeostasis against increasing sFlt-1 in preeclampsia. Furthermore, our results indicated that arginase inhibitor could be one of the future treatments targeting sFlt-1 for preeclampsia. This study is the first to report on the relationship between sFlt-1 and arginase. Arginase competes with NOS for the common catalyzing substrate and shifts the metabolism of arginine and urea. Therefore, inhibition of arginase may block the conversion of l-arginine to urea and increase NO synthesis. This result suggested that inhibition of arginase expression and activity on sFlt-1 administration leads to an increase in NOS activity and NO production. NO was reported to decrease sFlt-1 production significantly in hypoxic primary human trophoblast [22]. Therefore, we considered that sFlt-1 negatively regulated itself through inhibition of arginase in HUVECs. One of limitations of our study is the small number of samples. Therefore further research need to be followed in large scale. In conclusion, our findings suggested that a mechanism to maintain a homeostatic state exists; sFlt-1 negatively regulates itself through arginase in pregnancy and a decline in arginase levels leads to preeclampsia. Suppression of arginase owing to an increasing sFlt-1 reduces sFlt-1 itself (see Fig. 4). Moreover, these alterations suggest that arginase inhibitors could be a potential target for the prophylactic treatment of preeclampsia.
    Conflicts of interest
    Acknowledgments We would like to thank Editage (www.editage.jp) for English language editing.
    Introduction L-arginase (E.C 3.5.3.1, L-arginine amidinohydrolase, ARG), one of the urea-cycle enzymes, is a binuclear manganese cluster metalloenzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea [1], [2]. Arginase has roots in early life forms and is widely distributed in the five kingdoms of organisms as diverse as bacteria, yeasts, plants, invertebrates and vertebrates [3]. Arginases have been purified and characterized from a wide variety organisms [4]. Also, the crystal structure of arginases from many species has been solved, including those from Homo sapiens[5], Rattus norvegicus[6] and Bacillus caldovelox[7]. Mammalian arginase is active as a trimer, but some bacterial arginases are hexameric [8]. The enzyme requires a two-molecule metal cluster of manganese in order to maintain proper function. These Mn2+ ions coordinate with water, orienting and stabilizing the molecule by allowing water to act as a nucleophile and attack L-arginine, hydrolyzing it into ornithine and urea [9]. In most mammals, two isozymes of this enzyme exist: cytoplasmic urea cycle arginase I (ARG I) or liver arginase which is highly expressed in the liver primarily to carry out ureagenesis via ammonia detoxification [10], [11] and a second mitochondrial isoenzyme arginase II (ARG II) or nonhepatic arginase which is expressed in trace amounts in extra-hepatic tissues that lack a complete urea cycle, especially kidney, prostate gland, brain and lactating mammary gland [12] which is involved in L-arginine homeostasis [13] and regulating L-ornithine pools for subsequent biosynthetic transformations including the biosynthesis of polyamines, glutamate, proline [14] and controlling tissue level arginine for nitric oxide (NO) biosynthesis [15] by competing with inducible nitric oxide synthase (iNOS) for their common substrate, L-arginine, which is an important determinant of the inflammatory response in various organs and regulating nitric oxide-dependent apoptosis [14], [16], [17].