Protein Kinase C-α Activation Induces NF-ĸB-Dependent VCAM-1 Expression in Cultured Human Umbilical Vein Endothelial Cells Treated with Sera from Preeclamptic Patients

Jiang, Ruming; Teng, Yincheng; Huang, Yajuan; Gu, Jianhong; Li, Min

doi:10.1159/000261788

Cited by 10 publications

(5 citation statements)

References 81 publications

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“…PKCb is a predominant conventional isoform of the protein kinase C (PKC) family, and is a serine/threonine protein kinase known to be involved in various cellular signal transductions [13]. Although previous studies linked several members of the PKC family to the pathogenesis of preeclampsia and abnormal placental development [14][15][16][17], very little has been carried out on the specific role of PKCb in preeclampsia. In fact, the regulation of angiogenesis is one of the key roles of these multifunctional isoenzymes in the PKC family, including PKCb [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

The Inhibition of Protein Kinase C β Contributes to the Pathogenesis of Preeclampsia by Activating Autophagy

Zhao

Gong

et al. 2020

EBioMedicine

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Background: Preeclampsia is a devastating hypertensive disorder of pregnancy with unknown mechanism. Recent studies have considered abnormal autophagy as a new cellular mechanism for this disorder, while little is known about how autophagy is specifically involved and what factors are implicated. Here, we report a previously unrecognized preeclampsia-associated autophagic regulator, PKCb, that is involved in placental angiogenesis. Methods: PKCb levels were evaluated by quantitative real-time PCR, western blotting, immunofluorescence and by the analysis of public data. The autophagy-regulating role of PKCb inhibition in preeclampsia pathogenesis was studied in a mouse model, and in human umbilical vein endothelial cells (HUVECs) and human choriocarcinoma cells (JEG-3). Findings: PKCb was significantly downregulated in human preeclamptic placentas. In a mouse model, the selective inhibition of PKCb by Ruboxistaurin was sufficient to induce preeclampsia-like symptoms, accompanied by excessive autophagic flux and a disruption in the balance of pro-and anti-angiogenic factors in mouse placentas. In contrast, autophagic inhibition by 3-methyladenine partially normalized hypertension, proteinuria and placental angiogenic imbalance in PKCb-inhibited mice. Our in vitro experiments demonstrated that PKCb inhibition activated autophagy, thus blocking VEGFA-induced HUVEC tube formation and resulting in the significant upregulation of sFLT1 and downregulation of VEGFA in JEG-3 cells. Interpretation: These data support a novel model in which autophagic activation due to PKCb inhibition leads to the impairment of angiogenesis and eventually results in preeclampsia.

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Section: Introductionmentioning

confidence: 99%

The Inhibition of Protein Kinase C β Contributes to the Pathogenesis of Preeclampsia by Activating Autophagy

Zhao

Gong

et al. 2020

EBioMedicine

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“…Primary HUASMC cultures were established according to the tissue block culture method reported in previous studies. 8 , 11 HUASMC cultures were confirmed by immunofluorescence analysis of the trophoblast marker α-actin, using an anti-α-actin antibody followed by a PE-labeled secondary antibody (both from Santa Cruz, Dallas, TX, USA). Primary HUVEC cultures were established by the trypsin digestion method.…”

Section: Methodsmentioning

confidence: 99%

Preeclampsia serum-induced collagen I expression and intracellular calcium levels in arterial smooth muscle cells are mediated by the PLC-γ1 pathway

et al. 2014

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In women with preeclampsia (PE), endothelial cell (EC) dysfunction can lead to altered secretion of paracrine factors that induce peripheral vasoconstriction and proteinuria. This study examined the hypothesis that PE sera may directly or indirectly, through human umbilical vein ECs (HUVECs), stimulate phospholipase C-γ1-1,4,5-trisphosphate (PLC-γ1-IP3) signaling, thereby increasing protein kinase C-α (PKC-α) activity, collagen I expression and intracellular Ca2+ concentrations ([Ca2+]i) in human umbilical artery smooth muscle cells (HUASMCs). HUASMCs and HUVECs were cocultured with normal or PE sera before PLC-γ1 silencing. Increased PLC-γ1 and IP3 receptor (IP3R) phosphorylation was observed in cocultured HUASMCs stimulated with PE sera (P<0.05). In addition, PE serum significantly increased HUASMC viability and reduced their apoptosis (P<0.05); these effects were abrogated with PLC-γ1 silencing. Compared with normal sera, PE sera increased [Ca2+]i in cocultured HUASMCs (P<0.05), which was inhibited by PLC-γ1 and IP3R silencing. Finally, PE sera-induced PKC-α activity and collagen I expression was inhibited by PLC-γ1 small interfering RNA (siRNA) (P<0.05). These results suggest that vasoactive substances in the PE serum may induce deposition in the extracellular matrix through the activation of PLC-γ1, which may in turn result in thickening and hardening of the placental vascular wall, placental blood supply shortage, fetal hypoxia–ischemia and intrauterine growth retardation or intrauterine fetal death. PE sera increased [Ca2+]i and induced PKC-α activation and collagen I expression in cocultured HUASMCs via the PLC-γ1 pathway.

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“…Preeclamptic serum increases PKC signaling in cultured HUVECs [ 341 , 342 ]. Gestational hypoxia upregulates PKC in the uterine arteries of pregnant sheep [ 343 ].…”

Section: K Ca Channels and Uteroplacental Circulat...mentioning

confidence: 99%

Ca2+-Activated K+ Channels and the Regulation of the Uteroplacental Circulation

Zhang

2023

IJMS

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Adequate uteroplacental blood supply is essential for the development and growth of the placenta and fetus during pregnancy. Aberrant uteroplacental perfusion is associated with pregnancy complications such as preeclampsia, fetal growth restriction (FGR), and gestational diabetes. The regulation of uteroplacental blood flow is thus vital to the well-being of the mother and fetus. Ca2+-activated K+ (KCa) channels of small, intermediate, and large conductance participate in setting and regulating the resting membrane potential of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) and play a critical role in controlling vascular tone and blood pressure. KCa channels are important mediators of estrogen/pregnancy-induced adaptive changes in the uteroplacental circulation. Activation of the channels hyperpolarizes uteroplacental VSMCs/ECs, leading to attenuated vascular tone, blunted vasopressor responses, and increased uteroplacental blood flow. However, the regulation of uteroplacental vascular function by KCa channels is compromised in pregnancy complications. This review intends to provide a comprehensive overview of roles of KCa channels in the regulation of the uteroplacental circulation under physiological and pathophysiological conditions.

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Protein Kinase C-α Activation Induces NF-ĸB-Dependent VCAM-1 Expression in Cultured Human Umbilical Vein Endothelial Cells Treated with Sera from Preeclamptic Patients

Cited by 10 publications

References 81 publications

The Inhibition of Protein Kinase C β Contributes to the Pathogenesis of Preeclampsia by Activating Autophagy

The Inhibition of Protein Kinase C β Contributes to the Pathogenesis of Preeclampsia by Activating Autophagy

Preeclampsia serum-induced collagen I expression and intracellular calcium levels in arterial smooth muscle cells are mediated by the PLC-γ1 pathway

Ca2+-Activated K+ Channels and the Regulation of the Uteroplacental Circulation

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