Hyperglycemia down-regulates cGMP-dependent protein kinase I expression in first trimester cytotrophoblast cells

Abstract

Diabetes in pregnancy is associated with microvascular complications and a higher incidence of preeclampsia. The regulatory signaling pathways involving nitric oxide, cGMP, and cGMP-dependent protein kinase (PKG) have been shown to be down-regulated under diabetic conditions and contribute to the pathogenesis of vascular complications in diabetes. The present study was undertaken to investigate how high glucose concentrations regulate PKG expression in cytotrophoblast cells (CTBs). Human CTBs (Sw. 71) were treated with 45, 135, 225, 495, or 945 mg/dL glucose for 48 h. Some cells were pretreated with a p38 inhibitor (10 μM SB203580) or 10 μM rosiglitazone. After treatment, the cell lysates were subjected to measure the expression of protein kinase G1α (PKG1α), protein kinase G1β (PKG1β), soluble guanylate cyclase 1α (sGC1α), and soluble guanylate cyclase 1 β (sGC1β) by Western blot. Statistical comparisons were performed using analysis of variance with Duncan's post hoc test. The expressions of PKG1α, PKG1β, sGC1α, and sGC1β were significantly down-regulated (p < 0.05) in CTBs treated with >135 mg/dL glucose compared to basal (45 mg/dL). The hyperglycemia-induced down-regulation of cGMP and cGMP-dependent PKG were attenuated by the SB203580 or rosiglitazone pretreatment. Exposure of CTBs to excess glucose down-regulates cGMP and cGMP-dependent PKG, contributing to the development of vascular complications in diabetic mothers during pregnancy. The attenuation of hyperglycemia-induced down-regulation of PKG proteins by SB203580 or rosiglitazone pretreatment further suggests the involvement of stress signaling mechanisms in this process.

Pharmic Activation of PKG2 Alleviates Diabetes‐Induced Osteoblast Dysfunction by Suppressing PLCβ1‐Ca2+‐Mediated Endoplasmic Reticulum Stress

“…In this study, we focused on the expression of PKG2 in vitro and discovered that it was downregulated in diabetic-stimulated osteoblasts, which was proved by western blot and immunofluorescence. Similar to phenomenon appeared in osteoblasts, several studies have indicated the reduced PKG expression in cardiomyocytes [15,36] and cytotrophoblast cells [37] under diabetic conditions. In order to determine if promoting PKG2 expression is sufficient to protect osteoblasts from diabetes-induced dysfunction, we increased its activity by transfecting lentivirus and adding cinaciguat.…”

TNF-α elicits phenotypic and functional alterations of vascular smooth muscle cells by miR-155-5p–dependent down-regulation of cGMP-dependent kinase 1

“…PKG1 is predominantly expressed in cardiovascular tissues, whereas the expression of PKG2 is generally restricted to the brain, intestine, and kidneys (28), indicating that PKG1 may be more important than PKG2 in VSMC function associated with cardiovascular homeostasis. It has been demonstrated that PKG1 was down-regulated in pathological conditions of various cardiovascular disorders (4,7). Indeed, PKG1 expression was decreased in neointimal smooth muscle cells of swine and rat coronary arteries after balloon catheter injury (29,30), and this pathological process was blunted by adenoviral PKG1 gene delivery (30).…”

“…In physiological states, the sequential activation of the NO/cGMP/PKG1 pathway by communication between endothelial cells and VSMCs plays a key role in vascular homeostasis and remodeling. However, impairment of this pathway is directly associated with various vascular disorders, such as atherosclerosis, hypertension, and preeclampsia (2)(3)(4).…”

Differential response of placental cells to high D‐glucose and its impact on extracellular vesicle biogenesis and trafficking via small GTPase Ras‐related protein RAB‐7A

“…Our understanding of the active mechanisms in placental cells involved in pregnancy adaptations and their response to high glucose concentrations remains limited. Studies have shown that trophoblast cells exposed to high glucose exhibit the downregulation of cGMP‐dependent PKG, which may contribute to the vascular complications observed in diabetic mothers (Nguyen et al., 2015 ). Pathological changes in placental tissues have also been linked to issues with trophoblast viability and proliferation, indicating the impact of high glucose on the miR‑137/PRKAA1/IL‑6 axis (Peng et al., 2018 ).…”