The role of Sirtuin1–PPARγ axis in placental development and function

Pham, Jonathan; Rajan, Kanaga Arul Nambi; Li, Ping; Parast, Mana M.

doi:10.1530/jme-17-0315

Cited by 31 publications

(16 citation statements)

References 82 publications

(98 reference statements)

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“…Pre-eclampsia is a severe pregnancy-related complication with the onset of hypertension after week 20 of pregnancy. Pre-eclampsia is mainly characterized by inadequate trophoblasts invasion, which can be caused by autophagy, abnormal metabolism, inflammation, and oxidative stress [34][35][36]. However, the comprehensive mechanisms of PE remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Progesterone Attenuates SIRT1-Deficiency-Mediated Pre-Eclampsia

et al. 2022

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Pre-eclampsia is a severe hypertensive disorder of pregnancy (HDP), mainly characterized by new-onset hypertension with proteinuria after 20-week gestation. Sirtuin1 (SIRT1), a class III histone deacetylase, is associated with the regulation of various pathophysiological processes, including inflammation, immune response, metabolism, and autophagy. However, the effect of SIRT1 in the pathogenesis of pre-eclampsia remains to be elucidated. In this study, we found that the expression of SIRT1 was relatively lower in the placentas and serum samples of pre-eclampsia patients. Typical pre-eclampsia-like symptoms, such as hypertension, proteinuria, fetal growth restriction, kidney injury, and a narrow placental labyrinth layer, were observed in SIRT1 knockdown (SIRT1+/−) mice. Of note, these performances could be improved after the intraperitoneal injection of SIRT1 agonist SRT2104. More importantly, we found that the efficacy of progesterone on attenuating symptoms of PE was profoundly better than that of metformin in SIRT1+/− mice. In addition, our results suggested that progesterone can promote the invasion and inhibit the apoptosis of trophoblasts. These data suggest that SIRT1 plays an important role in pre-eclampsia and that progesterone alleviates pre-eclampsia-like symptoms mediated by SIRT1 deficiency.

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Section: Discussionmentioning

confidence: 99%

Progesterone Attenuates SIRT1-Deficiency-Mediated Pre-Eclampsia

et al. 2022

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“…Placental gene expression of TNF-α and HIF-1α was downregulated by citrulline supplementation. Citrulline upregulated the gene expression of SIRT1, which is an important stress-response protein that modulates feto-placental vascular development 44 (Figure 6C) . The gene expression of enzymes related to lipid metabolism, including the paraoxonase 2 (PON2), protein kinase AMP-Activated non-catalytic subunit gamma 2 (Prkag2), phospholipase A2 (Pla2) was recently reported differentially expressed in placentas between Sprague Dawley (SD) rats and DSSR 45 .…”

Section: Resultsmentioning

confidence: 99%

“…The expression of SIRT1, an nutrient sensor, is downregulated in preeclamptic women in comparison to healthy pregnant 97 . The SIRT1-peroxisome proliferator-activated receptor gamma (PPARγ) axis is proposed to be a key player in trophoblast differentiation and placental development 44 . The downregulation of SIRT1 expression in the placenta might be responsible for the increased NF-κB transcriptional activity and reduction of PPARγ 98 .…”

Section: Discussionmentioning

confidence: 99%

“…The downregulation of SIRT1 expression in the placenta might be responsible for the increased NF-κB transcriptional activity and reduction of PPARγ 98 . PPARγ is a transcription factor that is well-known for its key role in glucose and lipid metabolism 44 . These results suggest an important link between placental lipid metabolism and preeclampsia, which warrants further studies.…”

Section: Lipid Metabolismmentioning

confidence: 99%

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L-citrulline ameliorates pathophysiology in a rat model of superimposed preeclampsia

Man

Zhou

Lam

et al. 2021

Preprint

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Preeclampsia, characterized by hypertension, proteinuria, and fetal growth restriction, is one of the leading causes of maternal and perinatal mortality. By far, there is no effective pharmacological therapy for preeclampsia. The present study was conducted to investigate the effects of L-citrulline supplementation in Dahl salt-sensitive rat, a model of superimposed preeclampsia. Parental DSSR were treated with L-citrulline (2.5 g/L in drinking water) from the day of mating to the end of lactation period. Blood pressure of the rats was monitored throughout pregnancy and markers of preeclampsia were assessed. Endothelial function of the pregnant DSSR was assessed by wire myograph. L-citrulline supplementation significantly reduced gestational hypertension, proteinuria, and levels of circulating soluble fms-like tyrosine kinase 1 in DSSR. L-citrulline improved maternal endothelial function by augmenting the production of nitric oxide in the aorta and improving endothelium-derived hyperpolarizing factor-mediated vasorelaxation in resistance arteries. L-citrulline supplementation improved placental insufficiency and fetal growth, which were associated with an enhancement of angiogenesis and reduction of fibrosis and senescence in the placentas. In addition, L-citrulline downregulated genes involved in the toll-like receptor 4 and nuclear factor-κB signaling pathway. In conclusion, this study shows that L-citrulline supplementation reduces gestational hypertension, improves placentation and fetal growth in a rat model of superimposed preeclampsia. L-citrulline supplementation may represent an effective and safe therapeutic strategy for preeclampsia that benefit both the mother and the fetus.

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“…Placental gene expression of TNF-α and HIF-1α was downregulated by citrulline supplementation. Citrulline up-regulated the gene expression of SIRT1, which is an important stress-response protein that modulates feto-placental vascular development (Pham et al, 2018) (Figure 6c). The gene expression of enzymes related to lipid metabolism, including paraoxonase 2 (Pon2), protein kinase AMP-activated non-catalytic subunit γ2 (Prkag2), and phospholipase A 2 (Pla2), was recently reported to be differentially expressed in the placentas of Sprague-Dawley (SD) rats and DSSR (Maeda et al, 2019).…”

Section: Citrulline Regulates Differential Gene Expressions In Dssr P...mentioning

confidence: 99%

l‐Citrulline ameliorates pathophysiology in a rat model of superimposed preeclampsia

Man

Zhou

Lam

et al. 2022

British J Pharmacology

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Background and Purpose Preeclampsia, characterized by hypertension, proteinuria and restriction of fetal growth, is one of the leading causes of maternal and perinatal mortality. So far, there is no effective pharmacological therapy for preeclampsia. The present study was conducted to investigate the effects of supplementation with l‐citrulline in Dahl salt‐sensitive rats, a model of superimposed preeclampsia. Experimental Approach Parental Dahl salt‐sensitive rats were treated with l‐citrulline (2.5 g·L−1 in drinking water) from the day of mating to the end of lactation period. Blood pressure was monitored throughout pregnancy and markers of preeclampsia were assessed. Endothelial function of the pregnant Dahl salt‐sensitive rats was assessed by wire myograph. Key Results In Dahl salt‐sensitive rats, l‐citrulline supplementation significantly reduced maternal blood pressure, proteinuria and levels of circulating soluble fms‐like tyrosine kinase 1. l‐Citrulline improved maternal endothelial function by augmenting the production of nitric oxide in the aorta and improving endothelium‐derived hyperpolarizing factor‐mediated vasorelaxation in resistance arteries. l‐Citrulline supplementation improved placental insufficiency and fetal growth, which were associated with an enhancement of angiogenesis and reduction of fibrosis and senescence in the placentas. In addition, l‐citrulline down‐regulated genes involved in the TLR4 and NF‐κB signalling pathways. Conclusion and Implications This study shows that l‐citrulline supplementation reduced gestational hypertension and improved placentation and fetal growth in a rat model of superimposed preeclampsia. l‐Citrulline supplementation may provide an effective and safe therapeutic strategy for preeclampsia that benefits both the mother and the fetus.

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The role of Sirtuin1–PPARγ axis in placental development and function

Cited by 31 publications

References 82 publications

Progesterone Attenuates SIRT1-Deficiency-Mediated Pre-Eclampsia

Progesterone Attenuates SIRT1-Deficiency-Mediated Pre-Eclampsia

L-citrulline ameliorates pathophysiology in a rat model of superimposed preeclampsia

l‐Citrulline ameliorates pathophysiology in a rat model of superimposed preeclampsia

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