The Effect and Mechanism of Asymmetric Dimethylarginine Regulating Trophoblastic Autophagy on Fetal Growth Restriction.

Fetal growth restriction (FGR) is an important cause of perinatal death and adverse pregnancy outcomes. Asymmetric dimethylarginine (ADMA) is associated with FGR, but the mechanisms have not been thoroughly studied. Here, we determined the levels of ADMA and autophagy-related molecules in human blood samples and placental tissues. And we also used the human chorionic carcinoma cell line BeWo to investigate the mechanism of ADMA-induced FGR in vitro. Compared with the control group, ADMA levels in maternal blood and placenta were increased in patients with FGR, and the birth weight (BW) percentile was negatively correlated with maternal serum ADMA concentration in the FGR group. The expression of mammalian target of rapamycin (mTOR) in the placenta of the FGR group was lower than the control group, while the expression of Beclin-1 and microtubule-associated protein 1 light chain 3-II (LC3-II)/LC3-I was significantly increased in the FGR group. And the expression of matrix metalloproteinase 9 (MMP9) was decreased in the placenta of patients with FGR. In in vitro cell experiments, compared with the control group, the expression of mTOR and MMP9 in BeWo cells was decreased and the expression of Beclin-1 and LC3-II/LC3-I was increased in the ADMA-treated group. Moreover, ADMA had favorable effects on the formation of autophagic vacuoles, and the autophagy inhibitor 3-Methyladenine (3-MA) could reduce the autophagy-induction effect of ADMA on BeWo cells. This study found that ADMA could participate in the occurrence of FGR through inducing autophagy in trophoblasts.

The role and mechanism of asymmetric dimethylarginine in fetal growth restriction via interference with endothelial function and angiogenesis.

PURPOSE: Fetal growth restriction (FGR) is a high-risk pregnancy, and placental dysfunction is the main cause of FGR. The upregulation of asymmetric dimethylarginine (ADMA) is linked to FGR pathology, but the mechanism needs to be investigated. METHODS: The levels of ADMA and other related molecules were measured in human biological samples. We further used human umbilical vein endothelial cells (HUVECs) to reveal the mechanism of ADMA-induced FGR in vitro. RESULTS: Compared with the control group, FGR patients had higher placental resistance, and ADMA levels were increased in the maternal blood, cord blood, and placenta; additionally, nitric oxide (NO) production decreased, accompanied by a decreased expression of endogenous NO synthase (eNOS). The expression of vascular growth factor (VEGF) and placental growth factor (PLGF) in the maternal blood during the third trimester and umbilical cord of the FGR group was lower than the control group. The PLGF levels in the placentas of the FGR group were also reduced, while the expression of soluble fms-like tyrosine kinase-1 (sFlt-1) increased. In in vitro cell experiments, NO production was obviously lower when the cells were exposed to 100 µM of ADMA, with no difference in eNOS expression. There was a dose-dependent decrease in PLGF expression with increasing doses of ADMA, and the levels of sFlt-1 increased. Moreover, we confirmed that tube formation in HUVECs was lower after ADMA treatment compared with the control group. CONCLUSION: The accumulation of ADMA during pregnancy has an adverse effect on fetal development via interference with placental endothelial function and angiogenesis.

[Clinical study of trimetazidine for myocardial protection in acute myocardial infarction].

OBJECTIVE: To assess the effect of trimetazidine as an adjunctive treatment to reperfusion therapy in acute myocardial infarction. METHODS: Sixty patients with acute myocardial infarction were randomized to receive trimetazidine (a loading dose of 60 mg followed by 20 mg 3 times daily) for 2 weeks (n = 32) or to be controls (n = 28). The loading dose was started early before the reperfusion therapy. Patients received intermittent ST-segment monitoring to assess the resolution of ST-segment deviation one hour after reperfusion therapy. Venous blood samples for measurement of malondialdehyde (MDA) and endothelin (ET-1) were taken immediately on admission and 1, 4, 8, 24 and 48 hours as well as 7 days after reperfusion. In-hospital and 3-months major adverse cardiac events were recorded. RESULTS: Blinded ST-segment analysis showed that there was a more marked return towards baseline one hour after reperfusion therapy in the trimetazidine group, than in the control group [change (7.14 +/- 3.50) mm vs (3.79 +/- 1.32) mm, P = 0.041]. The measurement of plasma MDA showed that, there was a significantly lower level in the trimetazidine group 4, 8, 24, 48 hours and 7 days after reperfusion (P < 0.05). The level of plasma ET-1 was significantly lower in the trimetazidine group 8 hours and 7 days after reperfusion (P < 0.05). There was no side effect due to trimetazidine. Clinical outcomes were similar between the two groups. CONCLUSIONS: Trimetazidine is effective for the resolution of ST-segment elevation. The effect of trimetazidine against malondialdehyde and ET-1 formation suggested that it might be the mechanism of the myocardial protection.

[Analysis of spontaneous reperfusion in acute myocardial infarction and its effect on short-term prognosis].

OBJECTIVE: To analyse the clinical and angiographic characteristics of spontaneous reperfusion (SR) in AMI, and to evaluate its effect on short-term prognosis. METHODS: 112 consecutive AMI patients without intravenous thrombolytic therapy received emergent coronary angiography and primary PCI. The patients were divided into SR group (antegrade TIMI grade 2-3 flow) and non-SR group (antegrade TIMI grade 0-1 flow). The clinical, angiographic and prognostic features of the patients were analyzed. RESULTS: 31 patients (27.7%) were in SR group, and there was no significant difference in base-line clinical characteristics between the two groups. Compared with non-SR group, peak values of CK and CK-MB, Ventricular wall motion abnormality and mortality were lower in SR group, ejection fraction was higher in SR group. Logistic regression analysis showed that there was good correlation between SR and peak value of CK, collaterals, ventricular wall motion abnormality and pre-dilation in PCI. CONCLUSION: SR decreased infarction size, improved heart function and reduced 30-day mortality.