Potential mechanisms and serum biomarkers involved in sex differences in pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a disease associated with high mortality, but notable sex differences have been observed between males and females. For this reason, further research on the mechanisms underlying sex differences in PAH is required to better understand and treat the disease. This study mainly focused on gene expression levels to investigate potential differences in the pathogenesis and progression of PAH between the male and female sexes. Sex-specific differentially expressed genes (DEGs) were analyzed using the Gene Expression Omnibus datasets GSE117261 and GSE38267. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted, and a protein-protein interaction (PPI) network was established based on the identified DEGs to predict potential mechanisms involved in the observed sex differences in the pathogenesis of PAH. We identified 26 female- and 53 male-specific DEGs from lung tissue and 498 female-specific DEGs in blood samples. No male-specific DEGs were identified from blood samples. GO and KEGG pathway analyses revealed that female-specific DEGs in lung tissue were enriched in inflammatory response and cytokine-cytokine receptor interaction, whereas male-specific DEGs were mainly enriched in cellular chemotaxis and the nuclear factor of kappa light polypeptide gene enhancer in B-cell (NF-kappa B) signaling pathway. Lipocalin 2 (LCN2) was the only gene that was differentially expressed in both the lung tissue and the blood of female patients. In conclusion, inflammation and immunity may play key roles in the pathogenesis of female PAH, and LCN2 may act as a serum biomarker of female PAH, whereas the pathogenesis in males is more complicated.

Stress Reactivity, Susceptibility to Hypertension, and Differential Expression of Genes in Hypertensive Compared to Normotensive Patients

“…Using the PubMed database [ 69 ], we collected all the DEGs (of hypertensive compared with normotensive patients) that we could find ( Table 5 ). The total number of hypertension-related human DEGs found was 7865, as cited in the rightmost column of Table 5 [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ].…”

“…In this work, we analyzed all the publicly available independent experimental RNA-Seq datasets—on transcriptomes from the tissues of hypertensive versus normotensive patients [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ], hypertensive versus normotensive animals [ 7 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ], and domestic versus wild animals [ 72 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 ].…”

“…In this work, we analyzed all the publicly available independent experimental RNA-Seq datasets-on transcriptomes from the tissues of hypertensive versus normotensive patients [26][27][28][29][30][31][32][33][34][35][36][37][38][39], hypertensive versus normotensive animals [7,[40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57], and domestic versus wild animals [72,[176][177][178][179][180][181][182][183][184][185][186][187][188][189][190][191][192][193].…”

“…Parents of half of the hypertensive patients had hypertension, but all the known (>60) hypertension-related whole-genome human loci explained only 3% of this heritability of hypertension [ 25 ]. Maybe this is why mainstream transcriptome-profiling studies on hypertensive versus normotensive patients [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ] and animals [ 7 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ] are focused on the differentially expressed genes (DEGs) that are specific to gender, age, and the stage of hypertension development. This is needed in predictive preventive personalized participatory (4P) medicine [ 58 ] to estimate where, how, why, and when hypertension might occur in a given patient depending on his/her genetic background.…”

Lipocalin 2: could it be a new biomarker in pediatric pulmonary hypertension associated with congenital heart disease?

“…Takahashi and coworkers [16] found increased LCN2 expression in dermal microvascular endothelial cells and speculated this may contribute to PH progression in systemic sclerosis. Li et al [22] found LCN2 to be the only gene significantly expressed in females with PH. In our study, increased expression of LCN2 was as-sociated with PH and hence we postulate this may explain the increased incidence of pulmonary vascular disease associated with CHD.…”