Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 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

    • Introduction Preeclampsia a serious hypertensive

    2024-03-22

    Introduction Preeclampsia, a serious hypertensive disorder that can occur during pregnancy, is a pregnancy-related disease characterized by the onset of 6 ohda and proteinuria after the 20 t h week of gestation, and it occurs in about 5% of all pregnancies [1]. If left untreated, preeclampsia can sometimes lead to maternal and fetal morbidity and mortality. Despite numerous studies, no fundamental therapy is available, other than delivery of fetus and placenta, leading to an increased rate of preterm birth. Recently, several studies revealed that soluble fms-like tyrosine kinase-1 (sFlt-1), which inhibits placental growth factor (PLGF) and vascular endothelial growth factor (VEGF) in endothelial cells, is a key factor in the clinical onset of preeclampsia [2] and can be a therapeutic option for preeclampsia, such as pravastatin and apheresis [[3], [4], [5]]. Recently, a meta-analysis, the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SaPPhirE) study, revealed that the sFlt-1/PLGF ratio is a valuable predictive tool for preeclampsia [6]. The serum sFlt-1 level is beginning to increase from 11 to 9 weeks prior to the onset of preeclampsia in women who later develop preeclampsia. Soluble Flt-1 was known to gradually increase during pregnancy and exponentially around the onset of preeclampsia [7]. We hypothesized that there existed a system suppressing the sudden rise of sFlt-1 and that preeclampsia occurs by the collapse of the system. Arginase is known as an intracellular enzyme mediating nitric oxide synthase (NOS). It is composed of two subtypes, arginase 1 (cytosolic) and arginase 2 (mitochondrial), a hydrolytic enzyme responsible for the conversion of l-arginine to urea and l-ornithine [8]. Arginase competes with NOS for their common substrate l-arginine and, accordingly, is able to modulate nitric oxide (NO) production. A number of studies have highlighted the role of upregulation of arginase in the pathophysiology of endothelial dysfunction associated with animal models of hypertension [[9], [10], [11]]. In addition, arginase inhibitor, which could activate NOS, is of great interest as a potential therapeutic target to improve the development of pulmonary hypertension (PH). Arginase inhibitor prevents PH development in a guinea pig and rat [[12], [13], [14]]. In our study, the relationship between arginase and sFlt-1 was examined.
    Methods
    Results
    Discussion At first, higher sFlt-1 and arginase activity in plasma of HDP patients compared with NT patients (Fig. 1) was demonstrated. Body mass index (BMI) was higher in HDP patients than in NT patients (Table 1). Arginase was regarded as a novel marker for vascular complications of diabetes and was elevated in plasma of type 2 diabetic patients [17]. In this study, a type 2 diabetic patient was included in the HDP group. Thus far, we sub-analyzed except for that one patient. Our data demonstrated that no difference was observed in BMI of both groups and that the level of arginase activity was still higher in plasma of HDP patients compared with NT patients (Supplemental Table 1 and Fig. 1). We also found the difference of gestational week of delivery; however, the size of difference was small. Birth weight differed between the HDP and NT groups, partly because of the effect of placental dysfunction associated with preeclampsia. Next, our data demonstrated that administration of sFlt-1 to endothelial cells impaired arginase expression and activity. Circulating sFlt-1 binds and neutralizes VEGF and PLGF with high affinity. Circulating free sFlt-1 was thought to decrease when VEGF and PLGF bound to sFlt-1 are no longer available to their innate receptors on endothelial cells [18] [19]. Accordingly, rhVEGFR-1 (3000 pg/ml) administration in HUVECs resulted in a significant increase in the production of sFlt-1 itself after 48 h compared to that in untreated cells. Moreover, our results clearly demonstrated that rhVEGFR-1 (3000 pg/ml) treatment for 48 h significantly reduced arginase expression and its activity in HUVECs (Fig. 2). The condition reflected that in group 2. However, “group 3 status” is difficult to establish by administration of rVEGFR1 because HUVECs consistently produce VEGF and PLGF. Therefore, we adopted transfection of sFlt-1 to HUVECs.