MAO-A promoter polymorphism and idiopathic pulmonary arterial hypertension

Vadapalli, Shivani; Katta, Sujana; Sastry, B.K.S.; Nallari, Pratibha

doi:10.1007/s12041-011-0008-7

Cited by 19 publications

(26 citation statements)

References 14 publications

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“…Among the EC genes that were most differentially upregulated in IPAH: ENG, ORAI2, TFDP1, KDR, AMOTL2, PDGFB, FGFR1, EDN1, and NOTCH1 have been previously reported in the literature and support the broader validity of our results. [17][18][19][20][21][22][23] The Pulmonary Hypertension Breakthrough Initiative has provided the largest transcriptome study data to date. 16 Our data complement this study, representing the first close look at the transcriptomic landscape across IPAH lung cells in vivo, thus allowing for cellspecific analysis not possible with prior findings in cultured cells or whole lung transcriptomic analysis.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension

et al. 2020

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Despite recent improvements in management of idiopathic pulmonary arterial hypertension, mortality remains high. Understanding the alterations in the transcriptome–phenotype of the key lung cells involved could provide insight into the drivers of pathogenesis. In this study, we examined differential gene expression of cell types implicated in idiopathic pulmonary arterial hypertension from lung explants of patients with idiopathic pulmonary arterial hypertension compared to control lungs. After tissue digestion, we analyzed all cells from three idiopathic pulmonary arterial hypertension and six control lungs using droplet-based single cell RNA-sequencing. After dimensional reduction by t-stochastic neighbor embedding, we compared the transcriptomes of endothelial cells, pericyte/smooth muscle cells, fibroblasts, and macrophage clusters, examining differential gene expression and pathways implicated by analysis of Gene Ontology Enrichment. We found that endothelial cells and pericyte/smooth muscle cells had the most differentially expressed gene profile compared to other cell types. Top differentially upregulated genes in endothelial cells included novel genes: ROBO4, APCDD1, NDST1, MMRN2, NOTCH4, and DOCK6, as well as previously reported genes: ENG, ORAI2, TFDP1, KDR, AMOTL2, PDGFB, FGFR1, EDN1, and NOTCH1. Several transcription factors were also found to be upregulated in idiopathic pulmonary arterial hypertension endothelial cells including SOX18, STRA13, LYL1, and ELK, which have known roles in regulating endothelial cell phenotype. In particular, SOX18 was implicated through bioinformatics analyses in regulating the idiopathic pulmonary arterial hypertension endothelial cell transcriptome. Furthermore, idiopathic pulmonary arterial hypertension endothelial cells upregulated expression of FAM60A and HDAC7, potentially affecting epigenetic changes in idiopathic pulmonary arterial hypertension endothelial cells. Pericyte/smooth muscle cells expressed genes implicated in regulation of cellular apoptosis and extracellular matrix organization, and several ligands for genes showing increased expression in endothelial cells. In conclusion, our study represents the first detailed look at the transcriptomic landscape across idiopathic pulmonary arterial hypertension lung cells and provides robust insight into alterations that occur in vivo in idiopathic pulmonary arterial hypertension lungs.

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Section: Discussionmentioning

confidence: 99%

Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension

et al. 2020

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“…We cannot exclude this is a false-positive association as the nsSNP is located 2 amino acids downstream from the epitope of the CT-pro-ET-1-tracer, this may affect the antibody-epitope affinity. 4 rs5370 has previously been associated with idiopathic pulmonary arterial hypertension 29 and risk for hypertension. 30 In summary, using GWAS and in vitro functional follow-up, we report the involvement of the KKS system in the regulation of MR-pro-ADM and CT-pro-ET-1 plasma levels.…”

Section: Discussionmentioning

confidence: 98%

Genome-Wide Association Study on Plasma Levels of Midregional-Proadrenomedullin and C-Terminal-Pro-Endothelin-1

et al. 2013

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Abstract-Endothelin-1 (ET-1) and adrenomedullin (ADM) are circulating vasoactive peptides involved in vascular homeostasis and endothelial function. Elevated levels of plasma ET-1 and ADM, and their biologically stable surrogates, C-terminal-pro-endothelin-1 (CT-pro-ET-1) and midregional proadrenomedullin (MR-pro-ADM), are predictors of cardiac death and heart failure. We studied the association of common genetic variation with MR-pro-ADM and CTpro-ET-1 by genome-wide association analyses in 3444 participants of European ancestry. We performed follow-up genotyping of single nucleotide polymorphisms (SNPs) that showed suggestive or significant association in the discovery stage in additional 3230 participants. The minor variants in KLKB1 (rs4253238) and F12 (rs2731672), both part of the kallikrein-kinin system, were associated with higher MR-pro-ADM (P=4.46E-52 and P=5.90E-24, respectively) and higher CT-pro-ET-1 levels (P=1. 23E-122 and P=1.26E-67, respectively). Epistasis analyses showed a significant interaction between the sentinel SNP of F12 and KLKB1 for both traits. In addition, a variant near the ADM gene (rs2957692) was associated with MR-pro-ADM (P=1.05E-12) and a variant in EDN-1 (rs5370) was associated with CTpro-ET-1 (P=1.49E-27). The total phenotypic variation explained by the genetic variants was 7.2% for MR-pro-ADM and 14.6% for CT-pro-ET-1. KLKB1 encodes plasma kallikrein, a proteolytic enzyme known to cleave high-molecular-weight kininogen to bradykinin and prorenin to renin. We cloned the precursors of ADM and ET-1 and demonstrated that purified plasma kallikrein can cleave these recombinant proteins into multiple smaller peptides. The discovery of genetic variants in the kallikrein-kinin system and in the genes encoding pre-pro-ET-1 and pre-pro-ADM provides novel insights into the

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“…Expression studies have shown an absence of differences in endothelin‐1 levels between Asn (T allele) carriers and Lys (G allele) carriers. It has been suggested that this polymorphism is in linkage disequilibrium with other EDN1 variants/genes/environmental factors that may influence endothelin‐1 expression …”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that this polymorphism is in linkage disequilibrium with other EDN1 variants/ genes/environmental factors that may influence endothelin-1 expression. 1 Several theories have been proposed to explain the etiopathogenesis of SSNHL, including viral infection, vascular occlusion, breaks of labyrinthine membranes, immune-mediated mechanisms, and abnormal cellular stress responses within the cochlea. 24 Among the hypothesized pathologies of SSNHL, impaired inner ear perfusion and ischemic vascular damage of the cochlea are widely recognized as possible pathogenic mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Endothelin-1, which is known as an extremely potent vasoconstrictor peptide, is one of the prominent endothelial mediators. 1 It is widely distributed throughout the mammalian body in cardiovascular and noncardiovascular tissues, including the nervous system, 2,3 and is also expressed in the spiral modiolar artery, endolymphatic sac, vestibule, stria vascularis, and spiral ganglion cells. [4][5][6] The distribution provides a fair idea of how endothelin-1 functions in the inner ear.…”

Section: Introductionmentioning

confidence: 99%

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