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It has been accepted that pregnant women should receive antihypertensive therapy when the blood pressure is ≥160/110 mmHg (1 mmHg=0.133 kPa). However, a consensus is yet to be reached worldwide regarding whether lowering blood pressure is required for pregnant women with mild hypertension (blood pressure <160/110 mmHg). Diagnosis and treatment of hypertension and pre-eclampsia in pregnancy: a clinical practice guideline in China (2020) recommends that pregnant women whose blood pressure are ≥140/90 mmHg should be treated with antihypertensive therapy. A recent study has shown that antihypertensive therapy for pregnant women with blood pressure over 140/90 mmHg could improve the pregnancy outcomes, providing further evidence for the recommendation in the 2020 guideline in China. Current studies have shown that the risk of adverse pregnancy outcomes increases in pregnant women with normal high blood pressure (130-139/80-89 mmHg), which indicates that effective management measures such as close monitoring should be conducted for this population, in order to reduce the adverse pregnancy outcomes.
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Objective To explore the pathways of preeclampsia by investigating different effects of pravastatin (Pra) on and soluble FMS tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) in different preeclampsia (PE)?like mouse models. Methods C57BL/6J mice were randomly subcutaneously injected with N?nitro?L?arginine methyl ester (L?NAME) or intraperitoneally injected with lipopolysaccharide (LPS) as PE?like mouse model, saline as normal pregnancy control (Con) respectively, daily at gestational 7-18 days. Pra was given daily at gestational 8-18 days in each model group and the mice were divided into Pra (L?NAME+Pra, LPS+Pra, Con+Pra) and saline (L?NAME+NS, LPS+NS, Con+NS) groups. Liver,placental tissue and blood of pregnant mice were collected on the 18th day of pregnancy. The levels of VEGF, PlGF and sFlt?1 in the liver, placenta and serum of mice in each group were compared by western blot, ELISA and real?time fluorescence quantitative PCR (RT-PCR). Results (1) ELISA: Serum VEGF (205.70±3.43, 154.60±2.31) and PlGF (131.5±3.75, 101.50± 4.31) levels were significantly increased in L?NAME+Pra group compared with L?NAME+NS group (all P<0.05). Serum VEGF (202.30 ± 4.90, 144.50 ± 6.71) and PlGF (121.50 ± 3.86, 95.41 ± 4.08) levels were significantly higher in LPS+Pra group than those in LPS+NS group (all P<0.05). Serum sFlt?1 level in LPS+Pra group was significantly lower than that in LPS+NS group (3.01±0.50, 776.60±80.06), serum sFlt?1 level in L?NAME+Pra group was significantly lower than that in L?NAME+NS group (2.60±0.06, 583.70±9.83;all P<0.05). (2) Western blot: the expression levels of PlGF (1.344±0.118, 0.664±0.143) and VEGF (1.34±0.12, 0.66 ± 0.14) in the liver of mice in the L?NAME+Pra group were significantly higher than those in the L?NAME+NS group (all P<0.05), but the expression levels of PlGF and VEGF in the placenta of L?NAME+Pra group were not significantly different from those of L?NAME+NS group (all P>0.05). The expression levels of PlGF and VEGF in placenta and liver of pregnant mice in LPS+Pra group were not significantly different from those in LPS+N group (all P>0.05). (3) RT?PCR: the mRNA expression of PlGF and VEGF in placenta and liver of L?NAME+Pra group were not significantly different from those in L?NAME+NS group (all P>0.05). The mRNA expression levels of PlGF and VEGF in placenta and liver of LPS+Pra group were not significantly different from those of LPS+NS group (all P>0.05). Conclusions Pra has different regulatory effects on vascular endothelial function in different PE?like models. It reveals that different pathogenesis and pathways exist in different PE?like changes.
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Objective To explore whether pravastatin (Pra) inhibits mammalian target of rapamycin (mTOR) signal pathway by regulating Ras homolog enriched in brain (Rheb) protein through the comparison of gene and protein expression changes of Rheb in liver and placenta in preeclampsia (PE)-like mouse model treated with Pra. Methods C57BL/6J pregnant mice were randomly divided into two groups. The PE group was established by injecting N-nitro-L-arginine methyl ester (L-NAME) daily at gestational 7-18 days, saline was injected as contol group (Con);then giving mice Pra (PE+Pra, Con+Pra group, n=8) or normal saline (PE+N, Con+N group, n=8) every day from the 8th gestational day of pregnancy. The maternal liver and placenta tissues were collected on the 18th day of pregnancy. Western blot, real-time quantitative PCR and immunohistochemistry were used to compare the levels of Rheb protein and mRNA expression in the liver and placenta. Results (1)The results of western blot:there were no significant differences in Rheb protein expression between PE+N group (liver:0.706±0.123;placenta:0.866±0.128) and Con+N group (liver:0.732 ± 0.123; placenta: 0.909 ± 0.097), and the differences between PE+Pra group (liver: 0.669 ± 0.134;placenta:0.940 ± 0.221) and PE+N group were not significant either in liver or in placenta (all P>0.05). (2) The results of real-time quantitative PCR:when PE+N group (liver:1.026 ± 0.480;placenta:1.102 ± 0.361) compared with Con+N group (liver:1.058±0.389;placenta:1.067±0.400), PE+Pra group (liver:0.735±0.356;placenta:0.822±0.304) compared with PE+N group, there were no significant differences either in liver or in placenta (all P>0.05). (3) The results of immunohistochemistry: Rheb protein expression did not change significantly in maternal liver and placenta, there were no significant differences in protein expression levels between PE+N group and Con+N group, and between PE+Pra group and PE+N group (all P>0.05). Conclusion The inhibition of Pra on mTOR signaling pathway in some PE-like model may be independent of the expression of Rheb gene and protein.
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Objective@#To explore the pathways of preeclampsia by investigating different effects of pravastatin (Pra) on and soluble FMS tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) in different preeclampsia (PE)-like mouse models.@*Methods@#C57BL/6J mice were randomly subcutaneously injected with N-nitro-L-arginine methyl ester (L-NAME) or intraperitoneally injected with lipopolysaccharide (LPS) as PE-like mouse model, saline as normal pregnancy control (Con) respectively, daily at gestational 7-18 days. Pra was given daily at gestational 8-18 days in each model group and the mice were divided into Pra (L-NAME+Pra, LPS+Pra, Con+Pra) and saline (L-NAME+NS, LPS+NS, Con+NS) groups. Liver,placental tissue and blood of pregnant mice were collected on the 18th day of pregnancy. The levels of VEGF, PlGF and sFlt-1 in the liver, placenta and serum of mice in each group were compared by western blot, ELISA and real-time fluorescence quantitative PCR (RT-PCR).@*Results@#(1) ELISA: Serum VEGF (205.70±3.43, 154.60±2.31) and PlGF (131.5±3.75, 101.50±4.31) levels were significantly increased in L-NAME+Pra group compared with L-NAME+NS group (all P<0.05). Serum VEGF (202.30±4.90, 144.50±6.71) and PlGF (121.50±3.86, 95.41±4.08) levels were significantly higher in LPS+Pra group than those in LPS+NS group (all P<0.05). Serum sFlt-1 level in LPS+Pra group was significantly lower than that in LPS+NS group (3.01±0.50, 776.60±80.06), serum sFlt-1 level in L-NAME+Pra group was significantly lower than that in L-NAME+NS group (2.60±0.06, 583.70±9.83; all P<0.05). (2) Western blot: the expression levels of PlGF (1.344±0.118, 0.664±0.143) and VEGF (1.34±0.12, 0.66±0.14) in the liver of mice in the L-NAME+Pra group were significantly higher than those in the L-NAME+NS group (all P<0.05), but the expression levels of PlGF and VEGF in the placenta of L-NAME+Pra group were not significantly different from those of L-NAME+NS group (all P>0.05). The expression levels of PlGF and VEGF in placenta and liver of pregnant mice in LPS+Pra group were not significantly different from those in LPS+N group (all P>0.05). (3) RT-PCR: the mRNA expression of PlGF and VEGF in placenta and liver of L-NAME+Pra group were not significantly different from those in L-NAME+NS group (all P>0.05). The mRNA expression levels of PlGF and VEGF in placenta and liver of LPS+Pra group were not significantly different from those of LPS+NS group (all P>0.05).@*Conclusions@#Pra has different regulatory effects on vascular endothelial function in different PE-like models. It reveals that different pathogenesis and pathways exist in different PE-like changes.
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BACKGROUND@#Fatty acid oxidation (FAO) disorder is involved in the pathogenesis of some cases of preeclampsia (PE). Several studies show that mammalian target of rapamycin (mTOR) signaling pathway is related to FAO. Pravastatin (Pra) can promote FAO in Nω-nitro-L-arginine methyl ester (L-NAME) PE-like mouse model in our previous study. This study aimed to investigate the effect of mTOR signaling pathway in PE-like model treated with Pra.@*METHODS@#Pregnant mice were randomly injected with L-NAME as PE-like model group or saline as control group respectively, from gestational 7th to 18th day. Giving Pra (L-NAME + Pra, Control + Pra, n = 8) or normal saline (NS; L-NAME + NS, Control + NS, n = 8) from gestational 8th to 18th day, the mice were sacrificed on day 18 and their liver and placental tissues were collected. Then the activation of mTOR and its substrates in the liver and placenta were detected. And the association between mTOR activation and serum free fatty acid (FFA) levels and the expression of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) were evaluated using Pearson correlation test. Differences between groups were analyzed using independent t-test or one-way analysis of variance (ANOVA).@*RESULTS@#Both in the maternal liver and placenta, the activation of mTOR protein and its effect on substrates increased significantly in the L-NAME + NS group and decreased significantly in the L-NAME + Pra group. The p-mTOR/mTOR protein ratio decreased in the L-NAME + Pra group significantly than that in the L-NAME + NS group both in liver and placenta (liver: 0.74 ± 0.08 vs. 0.85 ± 0.06, t = 2.95, P < 0.05; placenta: 0.63 ± 0.06 vs. 0.77 ± 0.06, t = 4.64, P < 0.05). The activation of mTOR protein in the liver and placenta negatively correlated with the expression of LCHAD in the L-NAME + NS group (liver: r = -0.745, P < 0.05; placenta: r = -0.833, P < 0.05) and that in the maternal liver negatively correlated with the expression of LCHAD (r = -0.733, P < 0.05) and positively with the serum FFA levels (r = 0.841, P < 0.05) in the L-NAME + Pra group.@*CONCLUSION@#The inhibition of mTOR signaling pathway might be involved in the regulation of FAO in mouse model treated with Pra.
Subject(s)
Animals , Female , Mice , Pregnancy , Blotting, Western , Fatty Acids , Metabolism , Immunohistochemistry , Liver , Metabolism , Mice, Inbred C57BL , Oxidation-Reduction , Placenta , Metabolism , Pravastatin , Therapeutic Uses , Pre-Eclampsia , Drug Therapy , Signal Transduction , TOR Serine-Threonine Kinases , MetabolismABSTRACT
<p><b>Background</b>Pravastatin (Pra) exerts protective effects on preeclampsia. Preeclampsia is a multifactorial and pathogenic pathway syndrome. The present study compared the effects of Pra on clinical manifestations of preeclampsia in different pathogenic pathways.</p><p><b>Methods</b>Two different preeclampsia-like mouse models used in this study were generated with Nω-nitro-L-arginine methyl ester (L-NAME) and used lipopolysaccharide (LPS) from day 7 of gestation, respectively. Pra treatment was administered on day 2 after the models were established in each group (L-NAME + Pra, LPS + Pra, and Control + Pra, n = 8) or normal saline (NS) for the control group (L-NAME + NS, LPS + NS, and Control + NS, n = 8). Maternal weight, serum lipids, the histopathological changes, and lipid deposition in the liver and placenta were observed. The pregnancy outcomes were compared. The blood pressure analysis was carried out on repeated measurements of variance. Student's t-test was used for comparing the two groups. The enumeration data were compared by Chi-square test.</p><p><b>Results</b>The mean arterial pressure (MAP) and 24-h urinary protein in the L-NAME + NS and LPS + NS groups were significantly higher than the Control + NS group (F = 211.05 and 309.92 for MAP, t = 6.63 and 8.63 for 24-h urinary protein; all P < 0.05) and reduced in the L-NAME + Pra group as compared to the L-NAME + NS group (F = 208.60 for MAP, t = 6.77 for urinary protein; both P < 0.05). Urinary protein was decreased in the LPS + Pra group as compared to the LPS + NS group (t = 5.33; P < 0.05), whereas MAP had no statistical significance (F = 3.37; P > 0.05). Compared to the Control + NS group, the placental efficiency in the L-NAME + NS and LPS + NS groups decreased significantly (t = 3.09 and 2.89, respectively; both P < 0.05); however, no significant difference was observed in L-NAME + Pra and LPS + Pra groups (t = 1.37 and 0.58, respectively; both P > 0.05). Free fatty acid was elevated in the L-NAME + NS group as compared to the Control + NS group (t = 3.99; P < 0.05) at day 18 of pregnancy and decreased in the L-NAME + Pra group as compared to the L-NAME + NS group (t = 3.28; P < 0.05); however, no significant change was observed in the LPS model (F = 0.32; P > 0.05).</p><p><b>Conclusion</b>This study suggested that Pra affected the clinical manifestations differently in preeclampsia-like mouse models generated in various pathogenic pathways.</p>
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Objective To investigate the patency rate and restenosis after percutaneous transluminal angioplasty (PTA) for the treatment of arteriovenous fistula (AVF) and arteriovenous graft (AVG) stenosis in dialysis patients. Methods The patients who were successfully treated by PTA for the first time in the blood purification center of the 2nd Affiliated Hospital of Nanjing Medical University from January 2016 to June 2017, including 71 cases of AVF in the forearm, 52 cases of AVF in the upper arm and 59 cases of AVG were recorded. The data of different stenosis parts were analyzed before and after treatment and followed up for 12 months. The initial patency rate and assisted-PTA patency rate were observed at 3 months, 6 months, 9 months, and 12 months after ultrasound interventional therapy, and the initial patency time for patients who needed to reintervention among all types of pathways were recorded. Results The initial patency rates at 3 months, 6 months, 9 months and 12 months after ultrasound interventional therapy were 98.59％, 90.14％, 71.93％, 54.93％ respectively in forearm AVF, 90.38％, 65.38％, 42.31％, 32.69％ respectively in upper arm AVF, 91.53％, 32.20％, 6.78％, 1.69％ respectively in AVG, and the PTA-assisted patency rates were 98.59％, 97.18％, 95.77％, 94.37％ respectively in forearm AVF, 92.31％, 86.54％, 84.62％, 80.77％respectively in upper arm AVF, 100.00％, 98.31％, 96.61％, 93.22％ respectively in AVG, while the initial patency time was (8.99 ± 3.54) months in forearm AVF, (6.33 ± 3.01) months in upper arm AVF, (4.80 ± 1.40) months in AVG respectively. Conclusions Ultrasound can comprehensively evaluate the function of peripheral vascular access, guide PTA treatment, and evaluate treatment outcomes. Ultrasound intervention therapy has best initial patency rate for forearm AVF stenosis. The prognosis of upper arm AVF stenosis PTA is relatively poor due to the easy cephalic stenosis. Although AVG has a short interval of restenosis, it can achieve a better long-term patency rate through regular intervention with ultrasound intervention.
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Objective To investigate the modulation of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)expression by pravastatin in pre-eclampsia-like mouse model. Methods C57BL/6J mice were randomly injected with N-nitro-L-arginine methyl ester (L-NAME) as pre-eclampsia-like model group (PE) or saline as normal pregnancy control group(Con)respectively,from gestational the 7th to 18th day.For each group,pravastatin(PE+Pra,Con+Pra group)or saline(PE+N,Con+N Group)was given from the 8th to 18th day of gestation,respectively.Liver and placenta of pregnant mice were collected on gestational day 18.The LCHAD protein expression and mRNA levels of liver and placenta were detected through western blot, immunohistochemistry and real-time quantitative PCR. Results (1) The average arterial pressure of pregnant mice increased gradually from the 8th to 18th day in PE+N group,but decreased in PE+Pra group from gestational 10th day, 24 hour urinary protein levels in PE+N group [(1 494 ± 201) μg] were significantly higher than that in Con+N group[(935±128)μg,P<0.01],and also higher than that in PE+Pra group [(981 ± 116) μg, P<0.01].(2) The results of western blot: the expression of LCHAD was significantly lower in PE+N group(liver:0.64±0.11,placenta:0.48±0.06)than that in Con+N group(liver:1.06±0.10, placenta:0.60±0.10),and lower than that in PE+Pra group(liver: 0.99±0.04,placenta:0.60±0.08;all P<0.01).(3)The results of real-time quantitative PCR:the levels of LCHAD mRNA in liver and placenta in PE+N group (liver: 0.621 ± 0.128, placenta: 0.646 ± 0.129) were significantly decreased compared with Con+N group (liver: 1.007 ± 0.130, placenta: 1.004 ± 0.103; all P<0.01), but there was no significant difference between PE+Pra group (liver: 0.693 ± 0.678, placenta: 0.662 ± 0.183;P>0.05). (4) LCHAD protein was expressed widely and evenly in liver.The expression in placental cytotrophoblast and syncytial trophoblast cells located in outer layer of villous in labyrinth layer was the most. The expression of LCHAD was significantly lower in PE+N group(liver: 0.062±0.016,placenta:0.147±0.018)than that in Con+N group (liver: 0.126 ± 0.013, placenta: 0.183 ± 0.024), and lower than that in PE+Pra group (liver: 0.111 ± 0.017, placenta: 0.174 ± 0.027; all P<0.05). Conclusion Pravastatin could upregulate the LCHAD protein expression of liver and placenta in the pre-eclampsia-like mouse,which may be a mechanism to improve the clinical manifestations of pre-eclampsia.
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<p><b>BACKGROUND</b>The pathogenesis of some types of preeclampsia is related to fatty acid oxidation disorders. Rapamycin can regulate fatty acid metabolism. This study aimed to investigate the effects of rapamycin on the clinical manifestations and blood lipid parameters in different preeclampsia-like mouse models.</p><p><b>METHODS</b>Two preeclampsia-like mouse models and a control group were established: L-NA (injected with Nω-nitro-L-arginine methyl ester), LPS (injected with lipopolysaccharide), and the control group with normal saline (NS). The mouse models were established at preimplantation (PI), early- and late-pregnancy (EP, LP) according to the time of pregnancy. The administration of rapamycin (RA; L-NA+RA, LPS+RA, and NS+RA) or vehicle as controls (C; L-NA+C, LPS+C, NS+C) were followed on the 2nd day after the mouse models' establishment. Each subgroup consisted of eight pregnant mice. The mean arterial pressure (MAP), 24-h urinary protein, blood lipid, fetus, and placental weight were measured. The histopathological changes and lipid deposition of the liver and placenta were observed. Student's t-test was used for comparing two groups. Repeated measures analysis of variance was used for blood pressure analysis. Qualitative data were compared by Chi-square test.</p><p><b>RESULTS</b>The MAP and 24-h urinary protein in the PI, EP, and LP subgroups of the L-NA+C and LPS+C groups were significantly higher compared with the respective variables in the NS+C group (P < 0.05). The preeclampsia-like mouse models were established successfully. There was no significant difference in the MAP between the PI, EP, and LP subgroups of the L-NA+RA and L-NA+C groups and the LPS+RA and LPS+C groups. The 24-h urine protein levels in the PI and EP subgroups of the L-NA+RA group were significantly lower compared with the respective levels in the L-NA+C groups (1037 ± 63 vs. 2127 ± 593 μg; 976 ± 42 vs. 1238 ± 72 μg; bothP < 0.05), also this effect appeared similar in the PI and EP subgroups of the LPS+RA and LPS+C groups (1022 ± 246 vs. 2141 ± 432 μg; 951 ± 41 vs. 1308 ± 30 μg; bothP < 0.05). The levels of serum-free fatty acid (FFA) in the PI and EP subgroups of the L-NA+RA groups were significantly lower compared with the respective levels in the L-NA+C group (2.49 ± 0.44 vs. 3.30 ± 0.18 mEq/L; 2.23 ± 0.29 vs. 2.84 ± 0.14 mEq/L; bothP < 0.05). The levels of triglycerides (TG) and total cholesterol in the PI subgroup of the L-NA+RA group were significantly lower compared with the respective levels in the L-NA+C (1.51 ± 0.16 vs. 2.41 ± 0.37 mmol/L; 2.11 ± 0.17 vs. 2.47 ± 0.26 mmol/L; bothP < 0.05), whereas high-density lipoprotein serum concentration was significantly higher (1.22 ± 0.19 vs. 0.87 ± 0.15 mmol/L;P < 0.05) and low-density lipoprotein serum concentration did not exhibit a significant difference. There were no significant differences in the FFA of the PI, EP, and LP subgroups between the LPS+RA and the LPS+C groups. The levels of TG in the PI subgroup of the LPS+RA group were significantly lower compared with the respective levels in the LPS+C group (0.97 ± 0.05 vs. 1.22 ± 0.08 mmol/L;P < 0.05).</p><p><b>CONCLUSION</b>Rapamycin can improve clinical manifestations and blood lipid profile in part of the preeclampsia-like mouse models.</p>