Different Proteomic Profiles Regarding Antihypertensive Therapy in Preeclampsia Pregnant

Abstract

Preeclampsia (PE) is a hypertensive pregnancy syndrome associated with target organ damage and increased cardiovascular risks, necessitating antihypertensive therapy. However, approximately 40% of patients are nonresponsive to treatment, which results in worse clinical outcomes. This study aimed to compare circulating proteomic profiles and identify differentially expressed proteins among 10 responsive (R-PE), 10 nonresponsive (NR-PE) patients, and 10 healthy pregnant controls (HP). We also explored correlations between these proteins and clinical data. Plasma protein relative quantification was performed using mass spectrometry, followed by bioinformatics analyses with the UniProt database, PatternLab for Proteomics 4.0, and MetaboAnalyst software (version 6.0). Considering a fold change of 1.5, four proteins were differentially expressed between NR-PE and R-PE: one upregulated (fibronectin) and three downregulated (pregnancy-specific beta-1-glycoprotein 1, complement C4B, and complement C4A). Between NR-PE and HP, six proteins were differentially expressed: two upregulated (clusterin and plasmin heavy chain A) and four downregulated (apolipoprotein L1, heparin cofactor II, complement C4B, and haptoglobin-related protein). Three proteins were differentially expressed between R-PE and HP: one downregulated (transthyretin) and two upregulated (apolipoprotein C1 and hemoglobin subunit beta). These findings suggest a complex interplay of these proteins involved in inflammatory, immune, and metabolic processes with antihypertensive therapy responsiveness and PE pathophysiology.

Keywords: antihypertensive therapy responsiveness; complement C4A; complement C4B; fibronectin; preeclampsia; pregnancy-specific beta-1-glycoprotein 1; proteomics.

Figure 1

Chemometric and univariate statistical analyses of the proteins identified in the plasma of nonresponsive (NR-PE, in dark green) and responsive (R-PE, in light green) preeclampsia patients. (a) Two-dimensional partial least squares discriminant analysis (PLS-DA) score plot. (b) Three-dimensional sparse partial least squares-discriminant analysis (sPLS-DA) score plot. (c) Variable importance in projection (VIP) represents the score of the proteins that mostly contribute to the differentiation between the NR-PE and R-PE groups, as identified through sPLS-DA. (d) The volcano plot of the proteins showed four differentially expressed proteins when comparing the NR-PE with the R-PE group: three downregulated (PSG1, C4B, and C4A) and one upregulated (FN1). The red and blue boxes on the right indicate the relative amounts of the corresponding protein in each group under study. Boxplots of the four differentially expressed proteins in the plasma of the R-PE and NR-PE patients: (e) pregnancy-specific beta-1-glycoprotein 1, (f) complement C4B, (g) complement C4A, and (h) fibronectin. R-PE, responsive preeclampsia.; NR-PE, nonresponsive preeclampsia.

Figure 2

Chemometric and univariate statistical analyses of the proteins identified in the plasma of healthy pregnant (HP, in orange) women and nonresponsive preeclampsia (NR-PE, in dark green) patients. (a) Two-dimensional partial least squares discriminant analysis (PLS-DA) score plot. (b) Three-dimensional sparse partial least squares-discriminant analysis (sPLS-DA) score plot. (c) Variable importance in projection (VIP) represents the score of the proteins that mostly contribute to the differentiation between the HP and NR-PE groups, as identified through PLS-DA. (d) Volcano plot of the proteins showing that there were six differentially expressed proteins in NR-PE regarding HP: four downregulated (APOL1, SERPIND1, C4B, and HPR) and two upregulated (CLU and PLG). The red and blue boxes on the right indicate the relative amounts of the corresponding protein in each group under study. Boxplots of the six differentially expressed proteins in the plasma of HP women and NR-PE patients: (e) clusterin, (f) apolipoprotein L1, (g) heparin cofactor II, (h) plasmin heavy chain, (i) complement C4B, and (j) haptoglobin-related protein. HP, healthy pregnant; NR-PE, nonresponsive preeclampsia.

Figure 3

Chemometric and univariate statistical analyses of the proteins identified in the plasma of healthy pregnant (HP, in orange) women and responsive preeclampsia (R-PE, in light green) patients. (a) Two-dimensional partial least squares discriminant analysis (PLS-DA) score plot. (b) Three-dimensional sparse partial least squares-discriminant analysis (sPLS-DA) score plot. (c) Variable importance in projection (VIP) represents the score of the proteins that mostly contribute to the differentiation between the HP and R-PE groups, as identified through PLS-DA. (d) Volcano plot of the proteins showing that there were three upregulated proteins between the R-PE and HP groups: two upregulated (APOC1 and HBB) and one downregulated (TTR). The red boxes on the right indicate the relative amounts of the corresponding protein in each group under study. Boxplots of the three differentially expressed proteins in the plasma of HP women and R-PE patients: (e) apolipoprotein C1, (f) hemoglobin subunit beta, and (g) transthyretin. HP, healthy pregnant; R-PE, responsive preeclampsia.