Sexual Dimorphism of Metabolomic Profile in Arterial Hypertension

Abstract

Metabolomic studies have demonstrated the existence of biological signatures in blood of patients with arterial hypertension, but no study has hitherto reported the sexual dimorphism of these signatures. We compared the plasma metabolomic profiles of 28 individuals (13 women and 15 men) with essential arterial hypertension with those of a healthy control group (18 women and 18 men), using targeted metabolomics. Among the 188 metabolites explored, 152 were accurately measured. Supervised OPLS-DA (orthogonal partial least squares-discriminant analysis) showed good predictive performance for hypertension in both sexes (Q²cum = 0.59 in women and 0.60 in men) with low risk of overfitting (p-value-CV ANOVA = 0.004 in women and men). Seventy-five and 65 discriminant metabolites with a VIP (variable importance for the projection) greater than 1 were evidenced in women and men, respectively. Both sexes showed a considerable increase in phosphatidylcholines, a decrease in C16:0 with an increase in C28:1 lysophosphatidylcholines, an increase in sphingomyelins, as well as an increase of symmetric dimethylarginine (SDMA), acetyl-ornithine and hydroxyproline. Twenty-nine metabolites, involved in phospholipidic and cardiac remodeling, arginine/nitric oxide pathway and antihypertensive and insulin resistance mechanisms, discriminated the metabolic sexual dimorphism of hypertension. Our results highlight the importance of sexual dimorphism in arterial hypertension.

Figure 1

Global flow chart of the study design.

Figure 2

Scatter plots of multivariate analyses of metabolomics data. (A) First principal plan of the PCA performed on the global data set. No spontaneous grouping is evidenced; (B) Supervised OPLS-DA comparing hypertensive patients to controls in men with an overt separation of both groups; (C) Supervised OPLS-DA comparing hypertensive patients to controls in women showing similar good discrimination level between compared groups. The OPLS-DA models in both men and women provided a good fit for the data (R²Y = 0.97 in men and 0.95 in women), good predictive capability (Q²cum = 0.6 in men and 0.59 in women) and low risk of over-fitting (permQ² = −0.72, P-value CV-ANOVA = 0.009 in men and permQ² = −0.66, P-value CV-ANOVA = 0.005 in women). PC1, 2: first and second principal components; pLV: predictive latent variable; oLV 1: first orthogonal latent variable.

Figure 3

Word cloud visualization of the plasma metabolomic signature of hypertension in men and women. Word clouds were computed using metabolite VIPs to determine the size of the labels, and loadings to determine the color scale. Metabolites with negative loadings values (decreased in hypertension) are presented in brown, metabolites with positive loadings values (increased in hypertension) in green. Metabolites with a VIP < 1 are shown in gray.

Figure 4

Results of the univariate analysis for men (A) and women (B) represented as volcano plots. The x-axis represents fold changes for the mean of each metabolite concentration between hypertensive and normotensive individuals. Log-transformed P-values (log(P-value)) obtained after Student’s t-test between hypertensive and normotensive groups are contained in the y-axis using the greater retained P-values after BH correction (0.0064 and 0.019) as bases for the logarithms of P-values in men and women, repsectively. Only significantly different metabolites after BH correction (red dots) have log-transformed P-values ≥ 1 and are labelled. In lysophosphatidylcholines, hydroxysphingomyelins, phosphatidylcholines and acylcarnitines the length and the degree of unsaturation of the acyl moieties are separated by a colon and appear after the capital letter “C” in the short name of these molecules. Non-significant metabolites after BH correction appear as blue dots and are not labelled. Bubbles used to spot metabolites are colored according to the biochemical family as follows: light brown for acylcarnitines; green for amino acids; blue for biogenic amines; dark brown for lysophosphatidylcholines; orange for phosphatidylcholines and yellow for sphingomyelin.

Figure 5

Arginine/ornithine ratio. (A) Arginase activity, in hypertensive men and women, was calculated using the ratio of the average plasma concentrations of arginine/ornithine. (B) Arginine and ornithine metabolic pathways.

Figure 6

PC ae/PC aa ratio. The PC ae/PC aa ratio in hypertensive men and women was calculated from the average plasma concentrations of diacyl-phosphatidylcholines (PC aa) and acyl-alkyl-phosphatidylcholines (PC ae).

Figure 7

Integrative model of the common and sex-specific signatures and their main functional significance.