Detection and identification of factors in the atrium responsible for blood pressure regulation in patients with hypertension

Abstract

Resection of the left atrial appendage reportedly improves blood pressure in patients with hypertension. This study aimed to validate the transcriptional profiles of atrial genes responsible for blood pressure regulation in patients with hypertension as well as to identify the molecular mechanisms in rat biological systems. RNA sequencing data of left atrial appendages from patients with (n = 6) and without (n = 6) hypertension were subjected to unsupervised principal component analysis (PCA). Reduction of blood pressure was reflected by third and ninth principal components PC3 and PC9, and that eighteen transcripts, including endothelin-1, were revealed by PCA-based pathway analysis. Resection of the left atrial appendage in hypertensive rats improved their blood pressure accompanied by a decrease in serum endothelin-1 concentration. Expression of the endothelin-1 gene in the atrium and atrial appendectomy could play roles in blood pressure regulation in humans and rats.

Keywords: Atrial appendectomy; Blood pressure; Gene expression profile; Principal component analysis.

Fig. 1

Difference in gene expression profiles in left atrial tissues from the hypertension and normotension groups. (A) Volcano plot analysis of global mRNA changes in the hypertension group vs. normotension group. Each circle represents one mRNA; red circles are upregulated genes, and green circles are downregulated genes. The Y-axis shows the − log₁₀ values of the p-value. p values (0.05) and fold changes (2, 1/2) are indicated by red lines. (B) MA plot analysis of global mRNA changes in the hypertension group vs. normotension group. The x-axis denotes the average of log₂ expression value across samples normalized by transcripts per million, and the y-axis denotes the log₂ fold change in the given contrast. (C) MA plot analysis of the selected mRNAs that were significantly upregulated (red circles) and downregulated (green circles) in the hypertension group (p < 0.05)

Fig. 2

Heatmap of all expressed genes in each sample (samples 1–6 and 7–12 were from patients without and with hypertension, respectively). Rows, mRNAs; columns, patient number. Color ranges: higher, median, and lower expression is represented by red, orange, and yellow, respectively

Fig. 3

Principal component (PC) analysis to detect differences in segmental coordination between the hypertension and normotension groups. Red and blue circles represent PC vectors of the hypertension and normotension groups, respectively. In the combination of PC3 and PC9 (green square), vectors of the hypertension group gather in PC3 < 0 and PC9 < 0. In inset, PC scores of expressed genes in PC3 and PC9 are shown with PC vectors overlapping by arrows, where genes with scores of PC3 < 0 and PC9 < 0 (shown as black circles) were extracted for pathway analysis

Fig. 4

STRING analysis of predicted function partners for genes in the left atrial appendage of patients with hypertension. (A) Known interactions are shown in cyan lines (database) and in magenta lines (experimentally determined). Predicted interactions are shown in blue lines (gene co-occurrence). Others are shown in yellow lines (text-mining), in black lines (co-expression), and in purple lines (protein homology). (B, C, D) Association of the expression levels of EDN1 with ADRA2A (B), ADRA2B (C), and ADRA2C (D) with linear-regression analysis. Red circles for hypertension, and blue triangles for normotension patients

Fig. 5

Blood pressure changes after LAAE or sham operation in SHR. (A, B, C) Daily changes in systolic blood pressure (SBP) in (A), mean blood pressure (MBP) in (B), and diastolic blood pressure (DBP) in (C) before and after LAAE. Error bar of each plot indicates the range of standard deviation. (D, E, F) Postoperative change in SBP (D), MBP (E), and DBP (F) at day 3 and day 7 from baseline in each group. The horizontal line of the box indicates the median. The upper and lower edge of the box indicates the upper and lower quartiles, respectively. The upper and lower whisker indicates maximum and minimum, respectively

Fig. 6

Changes in serum ET–1 concentration after LAAE. Serum ET–1 concentrations were measured in SHR rats in the control (n = 8) and after LAAE on 7 POD (n = 5). The horizontal line of the box indicates the median. The upper and lower edge of the box indicates the upper and lower quartiles, respectively. The upper and lower whisker indicates maximum and minimum, respectively

Fig. 7

Visualized summary of the result demonstrating a role of atrial endothelin-1 as a potential factor responsible for blood pressure regulation. Resection of the atrial appendage may improve high blood pressure accompanied by a decrease in serum endothelin-1 concentration possibly upon relaxation of vasoconstriction