Molecular Characterization and Elucidation of Pathways to Identify Novel Therapeutic Targets in Pulmonary Arterial Hypertension

Abstract

Background: Pulmonary arterial hypertension (PAH) is a life-threatening chronic cardiopulmonary disease. However, there are limited studies reflecting the available biomarkers from separate gene expression profiles in PAH. This study explored two microarray datasets by an integrative analysis to estimate the molecular signatures in PAH.Methods: Two microarray datasets (GSE53408 and GSE113439) were exploited to compare lung tissue transcriptomes of patients and controls with PAH and to estimate differentially expressed genes (DEGs). According to common DEGs of datasets, gene and protein overrepresentation analyses, protein–protein interactions (PPIs), DEG–transcription factor (TF) interactions, DEG–microRNA (miRNA) interactions, drug–target protein interactions, and protein subcellular localizations were conducted in this study.Results: We obtained 38 common DEGs for these two datasets. Integration of the genome transcriptome datasets with biomolecular interactions revealed hub genes (HSP90AA1, ANGPT2, HSPD1, HSPH1, TTN, SPP1, SMC4, EEA1, and DKC1), TFs (FOXC1, FOXL1, GATA2, YY1, and SRF), and miRNAs (hsa-mir-17-5p, hsa-mir-26b-5p, hsa-mir-122-5p, hsa-mir-20a-5p, and hsa-mir-106b-5p). Protein–drug interactions indicated that two compounds, namely, nedocromil and SNX-5422, affect the identification of PAH candidate biomolecules. Moreover, the molecular signatures were mostly localized in the extracellular and nuclear areas.Conclusions: In conclusion, several lung tissue-derived molecular signatures, highlighted in this study, might serve as novel evidence for elucidating the essential mechanisms of PAH. The potential drugs associated with these molecules could thus contribute to the development of diagnostic and therapeutic strategies to ameliorate PAH.

The construction and analysis of m6A-related ceRNA network and patterns of immune infiltration in calcified aortic valve disease

“…Based on ceRNA network theory, miRNA expression should be increased. In pulmonary arterial smooth muscle cells (PASMC), inhibition of miR-17-5p inhibits PASMC proliferation and migration, while stimulation of miR-17-5p promotes collagen synthesis in PASMCs [45]. Due to the small sample size, our samples did not show positive results, despite in vitro experiments showing miR137 was involved in CAVD progression [23].…”

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.…”