Placental growth factor alleviates hyperglycemia-induced trophoblast pyroptosis by regulating mitophagy

Jun Tao; Yuzhu Rao; Jingjing Wang; Shiming Tan; Jinli Zhao; Zitong Cao; Lu He; Jun Meng; Peng Wu; Zuo Wang

doi:10.1111/jog.16050

Placental growth factor alleviates hyperglycemia-induced trophoblast pyroptosis by regulating mitophagy

J Obstet Gynaecol Res. 2024 Sep 17. doi: 10.1111/jog.16050. Online ahead of print.

Authors

Jun Tao¹, Yuzhu Rao¹, Jingjing Wang¹, Shiming Tan¹, Jinli Zhao², Zitong Cao¹, Lu He³, Jun Meng⁴, Peng Wu⁵, Zuo Wang¹

Affiliations

¹ Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, China.
² Emergency Department, The First Affiliated Hospital, University of South China, Hengyang, China.
³ Department of Obstetrics and Gynecology, The First Affiliated Hospital, University of South China, Hengyang, China.
⁴ Functional Department, The First Affiliated Hospital, University of South China, Hengyang, China.
⁵ Hengyang Maternal and Child Health Hospital, Hengyang, China.

PMID: 39288911
DOI: 10.1111/jog.16050

Abstract

Introduction: Hyperglycemia is closely related to trophoblast dysfunction during pregnancy and results in suppressed invasion, migration, and pro-inflammatory cell death of trophoblasts. Hyperglycemia is a dependent risk factor for gestational hypertension accompanied by decreased placental growth factor (PLGF), which is important for maternal and fetal development. However, there is currently a lack of evidence to support whether PLGF can alleviate trophoblast cell dysfunction caused by high blood sugar. Here, we aim to clarify the effect of hyperglycemia on trophoblast dysfunction and determine how PLGF affects this process.

Methods: The changes in placental tissue histomorphology from gestational diabetes mellitus (GDM) patients were compared with those of normal placentas. HTR8/SVneo cells were cultured in different amounts of glucose to examine cellular pyroptosis, migration, and invasion as well as PLGF levels. Furthermore, the levels of pyroptosis-related proteins (NLRP3, pro-caspase1, caspase1, IL-1β, and Gasdermin D [GSDMD]) as well as autophagy-related proteins (LC3-II, Beclin1, and p62) were examined by Western blotting. The GFP-mRFP-LC3-II system and transmission electron microscopy were used to detect mitophagy levels, and small interfering RNAs targeting BCL2 Interacting Protein 3 (siBNIP3) and PTEN-induced kinase 1 (siPINK1) were used to determine the role of mitophagy in pyroptotic death of HTR-8/SVneo cells.

Results: Our results show that hyperglycemia upregulates NLRP3, pro-caspase1, caspase1, IL-1β at the protein level in GDM patients. High glucose (HG, 25 mM) inhibits viability, invasion, and migration of trophoblast cells while suppressing superoxide dismutase levels and promoting malondialdehyde production, thus leading to a senescence associated beta-gal-positive cell burst. PLGF levels in nucleus and the cytosol are also inhibited by HG, whereas PLGF treatment inhibited pyroptosis-related protein levels of NLRP3, pro-caspase1, caspase1, IL-1β, and GSDMD, Gasdermin D N-terminal domain (GSDMD-N). HG-induced mitochondrial dysfunction and BNIP3 and PINK1/Parkin expression. Knocking down BINP3 and PINK1 abolished the protective role of PLGF by preventing mitophagy.

Conclusion: PLGF inhibited hyperglycemia, while PLGF reversed hyperglycemic injury by promoting mitophagy via the BNIP3/PINK1/Parkin pathway. Altogether, these results suggest that PLGF may protect against trophoblast dysfunction in diabetes.

Keywords: autophagy; gestational diabetes mellitus; pyroptosis; recombinant human placenta growth factor; trophoblast cells.

Abstract

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