AP39, a Modulator of Mitochondrial Bioenergetics, Reduces Antiangiogenic Response and Oxidative Stress in Hypoxia-Exposed Trophoblasts

Covarrubias, Ambart E.; Lecarpentier, Édouard; Lo, Agnes S.; Salahuddin, Saira; Gray, Kathryn J.; Karumanchi, S. Ananth; Zsengellér, Zsuzsanna K.

doi:10.1016/j.ajpath.2018.09.007

Cited by 56 publications

(35 citation statements)

References 91 publications

(33 reference statements)

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“…Interest is therefore increasing in characterizing the source of oxidative stress in preeclampsia to further define the therapeutic target. Oxidative stress arising from the mitochondria has emerged as an attractive target, and the use of mitochondrial-targeted antioxidants is now being investigated as a strategy to reverse oxidative stress in pre-eclampsia 210,211 .…”

Section: Antioxidantsmentioning

confidence: 99%

Pre-eclampsia: pathogenesis, novel diagnostics and therapies

et al. 2019

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Pre-eclampsia is a complication of pregnancy that is associated with substantial maternal and fetal morbidity and mortality. The disease presents with new-onset hypertension and often proteinuria in the mother, which can progress to multi-organ dysfunction, including hepatic, renal and cerebral disease, if the fetus and placenta are not delivered. Maternal endothelial dysfunction due to circulating factors of fetal origin from the placenta is a hallmark of pre-eclampsia. Risk factors for the disease include maternal comorbidities, such as chronic kidney disease, hypertension and obesity; a family history of pre-eclampsia, nulliparity or multiple pregnancies; and previous preeclampsia or intrauterine fetal growth restriction. In the past decade, the discovery and characterization of novel antiangiogenic pathways have been particularly impactful both in increasing understanding of the disease pathophysiology and in directing predictive and therapeutic efforts. In this Review, we discuss the pathogenic role of antiangiogenic proteins released by the placenta in the development of pre-eclampsia and review novel therapeutic strategies directed at restoring the angiogenic imbalance observed during pre-eclampsia. We also highlight other notable advances in the field, including the identification of long-term maternal and fetal risks conferred by pre-eclampsia.

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Section: Antioxidantsmentioning

confidence: 99%

Pre-eclampsia: pathogenesis, novel diagnostics and therapies

et al. 2019

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“…Additionally, its protective effect was seen on PCMs, supportively suggesting that AP39 protection is universal, independent of cell types. Indeed, AP39 protection has been demonstrated in many other types of cells …”

Section: Discussionmentioning

confidence: 99%

Supplementing preservation solution with mitochondria-targeted H2S donor AP39 protects cardiac grafts from prolonged cold ischemia–reperfusion injury in heart transplantation

Zhu

Juriasingani

et al. 2019

American Journal of Transplantation

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Heart transplant has been accepted as the standard treatment for end-stage heart failure. Because of its susceptibility to ischemia-reperfusion injury, the heart can be preserved for only 4 to 6 hours in cold static preservation solutions. Prolonged ischemia time is adversely associated with primary graft function and long-term survival. New strategies to preserve donor hearts are urgently needed. We demonstrate that AP39, a mitochondria-targeting hydrogen sulfide donor, significantly increases cardiomyocyte viability and reduces cell apoptosis/death after cold hypoxia/reoxygenation in vitro. It also decreases gene expression of proinflammatory cytokines and preserves mitochondria function. Using an in vivo murine heart transplant model, weshow that preserving donor hearts with AP39-supplemented University of Wisconsin solution (n = 7) significantly protects heart graft function, measured by quantitative ultrasound scan, against prolonged cold ischemia-reperfusion injury (24 hours at 4°C), along with reducing tissue injury and fibrosis. Our study demonstrates that

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“…Thus, mitochondrial dysfunction (leading to oxidative stress) plays a vital role in increased sFlt-1 production [ 76 ]. One study showed mitochondrial function can be improved by treatment with AP39 (a mitochondrion-targeted hydrogen sulfide donor), which ultimately reduced sFlt-1 levels by decreasing ROS levels and Hif-1α production [ 77 ]. Thus, mitochondria-targeted antioxidants can be used as therapeutics to alleviate PE symptoms.…”

Section: Pathogenesis Of Preeclampsiamentioning

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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AP39, a Modulator of Mitochondrial Bioenergetics, Reduces Antiangiogenic Response and Oxidative Stress in Hypoxia-Exposed Trophoblasts

Abstract: Disclosures: S.A.K. is a coinventor on patents related to angiogenic biomarkers that are held by Beth Israel Deaconess Medical Center. S.A.K. has financial interest in Aggamin LLC, which is developing therapies for preeclampsia.

Cited by 56 publications

References 91 publications

Pre-eclampsia: pathogenesis, novel diagnostics and therapies

Pre-eclampsia: pathogenesis, novel diagnostics and therapies

Supplementing preservation solution with mitochondria-targeted H2S donor AP39 protects cardiac grafts from prolonged cold ischemia–reperfusion injury in heart transplantation

Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta

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