Role of statin as inducer of Hmox-1 system in treatment of preeclampsia

Putra, Ridwan A; Effendi, Jusuf Sulaeman; Permadi, Wiryawan; Bandiara, Ria; Fauziah, Prima Nanda

doi:10.14715/cmb/2018.64.10.1

Cited by 14 publications

(9 citation statements)

References 23 publications

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“…A study of metformin showed it was able to prevent PE, reducing the production of sFlt-1 and sEng and ameliorating endothelial dysfunction through effects on mitochondria [ 202 ]. The protein statin exerts a protective effect on endothelial cells through induction of Hmox-1 expression and inhibition of sFlt-1 release, along with its antioxidant properties [ 203 ].…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

et al. 2020

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Preeclampsia (PE) is a serious pregnancy complication, affecting about 5–7% of pregnancies worldwide and is characterized by hypertension and damage to multiple maternal organs, primarily the liver and kidneys. PE usually begins after 20 weeks’ gestation and, if left untreated, can lead to serious complications and lifelong disabilities—even death—in both the mother and the infant. As delivery is the only cure for the disease, treatment is primarily focused on the management of blood pressure and other clinical symptoms. The pathogenesis of PE is still not clear. Abnormal spiral artery remodeling, placental ischemia and a resulting increase in the circulating levels of vascular endothelial growth factor receptor-1 (VEGFR-1), also called soluble fms-like tyrosine kinase-1 (sFlt-1), are believed to be among the primary pathologies associated with PE. sFlt-1 is produced mainly in the placenta during pregnancy and acts as a decoy receptor, binding to free VEGF (VEGF-A) and placental growth factor (PlGF), resulting in the decreased bioavailability of each to target cells. Despite the pathogenic effects of increased sFlt-1 on the maternal vasculature, recent studies from our laboratory and others have strongly indicated that the increase in sFlt-1 in PE may fulfill critical protective functions in preeclamptic pregnancies. Thus, further studies on the roles of sFlt-1 in normal and preeclamptic pregnancies are warranted for the development of therapeutic strategies targeting VEGF signaling for the treatment of PE. Another impediment to the treatment of PE is the lack of suitable methods for delivery of cargo to placental cells, as PE is believed to be of placental origin and most available therapies for PE adversely impact both the mother and the fetus. The present review discusses the pathogenesis of PE, the complex role of sFlt-1 in maternal disease and fetal protection, and the recently developed placenta-targeted drug delivery system for the potential treatment of PE with candidate therapeutic agents.

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Section: Therapeutic Approachesmentioning

confidence: 99%

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

et al. 2020

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“…preeclampsia is based on animal studies showing that pravastatin (3-hydroxy-3-methylglutaryl coenzyme-A-reductase inhibitor) has a protective role at the uteroplacental interface and in endothelial cells 21,24 . It was initially proposed by Ahmed et al that pravastatin protects vascular endothelial cells by inducing the expression of Hemeoxygenase-1 (HO-1), and as such inhibiting cytokine mediated release of the anti-angiogenic factors sFlt-1 and sEng 4,[25][26][27] . Decreased levels of sFlt-1 and sEng will increase the free PlGF and VEGF in placental and endothelial cells.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

INOVASIA Study: A Multicenter Randomized Clinical Trial of Pravastatin to Prevent Preeclampsia in High-Risk Patients

et al. 2022

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Objective To determine if treatment with pravastatin prevents preeclampsia in pregnant patients at risk for preeclampsia. Material & Methods The study was performed in four major tertiary hospitals in Surabaya, Bandung, and Makassar between 2017-2021. Pregnant women at high risk of developing preeclampsia were recruited and randomized into an intervention group and control group. The control group received low dose aspirin (80 mg) and calcium (1 g) daily, while the intervention group received additional pravastatin (20 mg twice daily) started from 14-20 weeks’ gestation until delivery. The pregnancy was followed until delivery, and the clinical data was collected. The primary outcome was the occurrence of preeclampsia. Result A total of 173 people participated in this study, including 86 in the control group and 87 in the pravastatin group. The pravastatin group had a significantly lower rate of preterm preeclampsia (13.8% vs 26.7%; p=0.034; (OR=0.034, 95% CI: 0.202-0.905) and preterm birth (16.1 % vs. 36 %; p=0.003; OR= 0.340, 95% CI: 0.165-0.7), mostly indicated preterm birth. Preeclampsia occurs later in the pravastatin group than in the control group (36.39+2.32 vs 34.89+3.38 weeks, p=0.048). Overall the pravastatin group had better perinatal outcomes. Neonates with low Apgar scores (<7) at 1 minute (5.7% vs 25.6%, p=0.000) and 5 minutes (2.3% vs 25.6%, p=0.028) were significantly less common in the pravastatin group. Additionally, the rate of low birthweight babies (< 2500g) was lower in pravastatin group (27.6% vs 40.7%; p= 0.069). Conclusion Pravastatin (20 mg bid) significantly reduces the risk for preterm preeclampsia and preterm birth in women at a high risk of developing preeclampsia.

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“…The rationale to use statin as a drug for preeclampsia is based on animal studies showing that pravastatin (3-hydroxy-3-methylglutaryl coenzyme-A-reductase inhibitor) has a protective role at the uteroplacental interface and on vascular cells (17,20,21). Pravastatin may protect endothelial cells, by inducing the expression of HO-1 and as such inhibiting cytokine mediated release of the anti-angiogenic factors sFlt-1 and sEng (18,19,(22)(23)(24)(25)(26)(27).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

INOVASIA Study: A Randomized Open Controlled Trial to Evaluate Pravastatin to Prevent Preeclampsia and Its Effects on sFlt1/PlGF Levels

Akbar

Yosediputra

Pratama³

et al. 2021

Am J Perinatol

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Objectives To evaluate the effect of pravastatin to prevent preeclampsia (PE) in pregnant women at a high risk of developing preeclampsia and the maternal and perinatal outcomes and the sFlt1/PLGF ratio. Study Design This is an open labelled RCT part of INOVASIA trial. Pregnant women at a high risk of developing PE were recruited and randomized into an intervention group (40) and a control group (40). The inclusion criteria consisted of pregnant women with positive clinical risk factor and abnormal uterine artery doppler examination at 10-20 weeks gestational age. The control group received low dose aspirin (80 mg/day) and calcium (1 g/day), while the intervention group received additional pravastatin (20 mg twice daily) starting from 14-20 weeks gestation until delivery. Research blood samples were collected before the first dose of pravastatin and before delivery. The main outcome was the rate of maternal preeclampsia, maternal-perinatal outcomes, and sFlt-1, PLGF, sFlt-1/PlGF ratio and sEng levels. Results The rate of preeclampsia was (non-significantly) lower in the pravastatin group compared with the control group (17.5% vs 35%). The pravastatin group also had a (non-significant) lower rate of severe preeclampsia, HELLP syndrome, acute kidney injury and severe hypertension. The rate of (iatrogenic) preterm delivery was significantly (p=0.048) lower in the pravastatin group (n=4) compared with the controls (n=12). Neonates in the pravastatin group had significantly higher birthweights (2931 + 537 vs 2625 + 872 g; p=0.006), lower Apgar scores < 7 (2.5 vs 27.5%, p=0.002), composite neonatal morbidity (0 vs 20%, p=0.005) and NICU admission rates (0 vs 15%, p=0.026). All biomarkers show a significant deterioration in the control group compared with non significant changes in the pravastatin group. Conclusions Pravastatin holds promise in the secondary prevention of preeclampsia and placenta-mediated adverse perinatal outcomes by improving the angiogenic imbalance.

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Role of statin as inducer of Hmox-1 system in treatment of preeclampsia

Cited by 14 publications

References 23 publications

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

INOVASIA Study: A Multicenter Randomized Clinical Trial of Pravastatin to Prevent Preeclampsia in High-Risk Patients

INOVASIA Study: A Randomized Open Controlled Trial to Evaluate Pravastatin to Prevent Preeclampsia and Its Effects on sFlt1/PlGF Levels

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