Personalized Therapy Against Preeclampsia by Replenishing Placental Protein 13 (PP13) Targeted to Patients With Impaired PP13 Molecule or Function

Abstract

Hypertensive disorders affect about one third of all people aged 20 and above, and are treated with anti-hypertensive drugs. Preeclampsia (PE) is one form of such disorders that only develops during pregnancy. It affects ten million pregnant women globally and additionally causes fetal loss and major newborn disabilities. The syndrome's origin is multifactorial, and anti-hypertensive drugs are ineffective in treating it. Biomarkers are helpful for predict its development. Generic drugs, such as low dose aspirin, were proven effective in preventing preterm PE. However, it does not cure the majority of cases and many studies are underway for fighting PE with extended use of additional generic drugs, or through new drug development programs.This review focuses on placental protein 13 (PP13). This protein is only expressed in the placenta. Impaired PP13 DNA structure and/or its reduced mRNA expression leads to lower blood PP13 level that predict a higher risk of developing PE. Two polymorphic PP13 variants have been identified: (1) The promoter PP13 variant with an “A/A” genotype in the -98 position (versus “A/C” or “C/C”). Having the “A/A” genotype is coupled to lower PP13 expression, mainly during placental syncytiotrophoblast differentiation and, if associated with obesity and history of previous preeclampsia, it accurately predicts higher risk for developing the disorder. (2) A thymidine deletion at position 221 causes a frame shift in the open reading frame, and the formation of an early stop codon resulting in the formation of DelT221, a truncated variant of PP13. In pregnant rodents, both short- and long- term replenishment of PP13 causes reversible hypotension and vasodilation of uterine vessels. Long-term exposure is also accompanied by the development of larger placentas and newborns. Also, only w/t PP13 is capable of inducing leukocyte apoptosis, providing maternal immune tolerance to pregnancy.Based on published data, we propose a targeted PP13 therapy to fight PE, and consider the design and conduct of animal studies to explore this hypothesis. Accordingly, a new targeted therapy can be implemented in humans combining prediction and prevention.

Maternal Serum Placental Protein-13 Levels in the Prediction of Pregnancies with Abnormal Invasive Placentation

“…Endothelial adaptation cannot be achieved in the first trimester due to placental development insufficiency (low PP-13 level), and increased placental factors (high PP-13 level) negatively affect the maternal endothelium in the later stages of pregnancy. Meiri et al showed that inadequate placentation in preeclampsia could be treated by replenishing PP-13 in the early stages of pregnancy [35]. In our study, the irregularly increased interstitial extravillous syncytiotrophoblast activity in pregnant women with AIP may have had increased PP-13 expression.…”

Galectin 13 (PP13) Facilitates Remodeling and Structural Stabilization of Maternal Vessels during Pregnancy

“…Based on all the above we propose a targeted PP13 therapy to fight preeclampsia in patients with impaired PP13 and high risk to develop preeclampsia [106]. These patients could receive PP13 as a nourishing drug to support uterine vessel expansion and stabilization of blood supply during pregnancy.…”

Placental protein 13

“…It specifically binds to G regions at À98 position than to A in the promoter region and induces promoter expression as revealed by PP13 promoter reporter expression studies after transfecting BeWo cells with PP13 having "A" or "C" in the À98 promoter position. 65 Decreased placental expression of glial cell missing-1 and estrogen-related receptor g genes, encoding transcription factors, regulates LGALS13 expression in the syncytiotrophoblast which is associated with trophoblast fusion and syncytium formation. 18 According to the available literature, the following few studies clearly demonstrate that decreased PP13 level or impairment in expression and its possible genetic causes are seen in women with preterm preeclampsia.…”

“…This suggests that PP13 may have a potential therapeutic role during pregnancy risk. 65 Phosphorylation of the protein side chains of PP13 expressed and purified from placenta indicated the specific biological function and necessitates further research in order to understand the role that the phosphorylated protein plays and its mechanism. The inherent biological property restored on wild-type PP13 and PP13-R studied and compared by phosphorus-31 nuclear magnetic resonance analysis and found that both variants exhibited weak endogenous lysophospholipase activity.…”

“…It specifically binds to G regions at −98 position than to A in the promoter region and induces promoter expression as revealed by PP13 promoter reporter expression studies after transfecting BeWo cells with PP13 having “A” or “C” in the −98 promoter position. 65…”