The Impact of Sex Chromosomes in the Sexual Dimorphism of Pulmonary Arterial Hypertension
2022; Elsevier BV; Volume: 192; Issue: 4 Linguagem: Inglês
10.1016/j.ajpath.2022.01.005
ISSN1525-2191
AutoresDan Predescu, Babak Mokhlesi, Sanda Predescu,
Tópico(s)Cardiovascular, Neuropeptides, and Oxidative Stress Research
ResumoPulmonary arterial hypertension (PAH) is a sex-biased disease with a poorly understood female prevalence. Emerging research suggests that nonhormonal factors, such as the XX or XY sex chromosome complement and sex bias in gene expression, may also lead to sex-based differences in PAH incidence, penetrance, and progression. Typically, one of females' two X chromosomes is epigenetically silenced to offer a gender-balanced gene expression. Recent data demonstrate that the long noncoding RNA X-inactive specific transcript, essential for X chromosome inactivation and dosage compensation of X-linked gene expression, shows elevated levels in female PAH lung specimens compared with controls. This molecular event leads to incomplete inactivation of the females' second X chromosome, abnormal expression of X-linked gene(s) involved in PAH pathophysiology, and a pulmonary artery endothelial cell (PAEC) proliferative phenotype. Moreover, the pathogenic proliferative p38 mitogen-activated protein kinase/ETS transcription factor ELK1 (Elk1)/cFos signaling is mechanistically linked to the sexually dimorphic proliferative response of PAECs in PAH. Apprehending the complicated relationship between long noncoding RNA X-inactive specific transcript and X-linked genes and how this relationship integrates into a sexually dimorphic proliferation of PAECs and PAH sex paradox remain challenging. We highlight herein new findings related to how the sex chromosome complement and sex-differentiated epigenetic mechanisms to control gene expression are decisive players in the sexual dimorphism of PAH. Pharmacologic interventions in the light of the newly elucidated mechanisms are discussed. Pulmonary arterial hypertension (PAH) is a sex-biased disease with a poorly understood female prevalence. Emerging research suggests that nonhormonal factors, such as the XX or XY sex chromosome complement and sex bias in gene expression, may also lead to sex-based differences in PAH incidence, penetrance, and progression. Typically, one of females' two X chromosomes is epigenetically silenced to offer a gender-balanced gene expression. Recent data demonstrate that the long noncoding RNA X-inactive specific transcript, essential for X chromosome inactivation and dosage compensation of X-linked gene expression, shows elevated levels in female PAH lung specimens compared with controls. This molecular event leads to incomplete inactivation of the females' second X chromosome, abnormal expression of X-linked gene(s) involved in PAH pathophysiology, and a pulmonary artery endothelial cell (PAEC) proliferative phenotype. Moreover, the pathogenic proliferative p38 mitogen-activated protein kinase/ETS transcription factor ELK1 (Elk1)/cFos signaling is mechanistically linked to the sexually dimorphic proliferative response of PAECs in PAH. Apprehending the complicated relationship between long noncoding RNA X-inactive specific transcript and X-linked genes and how this relationship integrates into a sexually dimorphic proliferation of PAECs and PAH sex paradox remain challenging. We highlight herein new findings related to how the sex chromosome complement and sex-differentiated epigenetic mechanisms to control gene expression are decisive players in the sexual dimorphism of PAH. Pharmacologic interventions in the light of the newly elucidated mechanisms are discussed. Pulmonary arterial hypertension (PAH) is a sex-biased disease characterized by pulmonary artery remodeling and hallmark plexiform lesions, leading to right heart failure and untimely death.1Montani D. Gunther S. Dorfmuller P. Perros F. 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Pulmonary artery endothelium resident endothelial colony-forming cells in pulmonary arterial hypertension.Pulm Circ. 2011; 1: 475-486Crossref PubMed Google Scholar Notch3, a member of the Notch receptor family, is expressed only in arterial smooth muscle cells of the human vasculature; and its signaling controls their proliferation.19Thistlethwaite P.A. Li X. Zhang X. Notch signaling in pulmonary hypertension.Adv Exp Med Biol. 2010; 661: 279-298Crossref PubMed Scopus (0) Google Scholar Recent studies of lung tissue of PAH patients and rodent models of PAH demonstrated elevated expression of Notch3 that correlate with the severity of the disease.8Li X. Zhang X. Leathers R. Makino A. Huang C. Parsa P. Macias J. Yuan J.X. Jamieson S.W. Thistlethwaite P.A. Notch3 signaling promotes the development of pulmonary arterial hypertension.Nat Med. 2009; 15: 1289-1297Crossref PubMed Scopus (246) Google Scholar Moreover, mice deficient in the C-C chemokine ligand type 2 exposed to chronic hypobaric hypoxia develop spontaneous PAH, via increased Notch3 signaling.20Yu Y.R. Mao L. Piantadosi C.A. Gunn M.D. CCR2 deficiency, dysregulation of Notch signaling, and spontaneous pulmonary arterial hypertension.Am J Respir Cell Mol Biol. 2013; 48: 647-654Crossref PubMed Scopus (0) Google Scholar Furthermore, Notch3 knockout mice are resistant to hypoxia-induced PAH, whereas blocking Notch signaling prevents pulmonary hypertensive vascular pathology in vivo. More sex-specific analyses are needed to provide additional information on Notch3 possible involvement in PAH sex paradox. PAH, a cause of pulmonary hypertension (PH), is classified as group I PH by the World Health Organization.21Simonneau G. Gatzoulis M.A. Adatia I. Celermajer D. Denton C. Ghofrani A. 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Haemodynamic definitions and updated clinical classification of pulmonary hypertension.Eur Respir J. 2019; 53: 1801913Crossref PubMed Scopus (1446) Google Scholar Briefly, the revised hemodynamic assessment suggests a new pressure level to define an abnormal elevation in the mean pulmonary artery pressure (>20 mmHg) and the need for pulmonary vascular resistance ≥3 Wood units to define the presence of precapillary PH. The updated classification maintain the five PH diagnostic groups; however, several separate entities are added in group I (PAH) that includes three new subgroups: drug and toxin-induced PAH, PAH patients who are long-term responders to calcium channel blockers and PAH with overt features of venous/capillary involvement, such as heritable pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, resulting from eukaryotic translation initiation factor 2 α kinase 4 or other gene mutations, and PAH associated with occupational exposure, in particular organic solvents. Moreover, group 5 is simplified by removing splenectomy and thyroid disorder and classification of several conditions (lymphangioleiomyomatosis-associated PH, with other parenchymal lung diseases). Despite revisions, it became clear that more studies are needed to better understand various conditions associated with PH and disease development. Population-based studies show a female prevalence in PAH of around 2 to 4 over men for all races and ethnicities and across all ages that have been studied to date.24Batton K.A. Austin C.O. Bruno K.A. Burger C.D. Shapiro B.P. Fairweather D. Sex differences in pulmonary arterial hypertension: role of infection and autoimmunity in the pathogenesis of disease.Biol Sex Differ. 2018; 9: 15Crossref PubMed Scopus (36) Google Scholar Although sex is the leading risk factor for the disease, other factors, such as infections, autoimmune diseases, inflammation, obesity, sleep apnea, and genetic predisposition, may be associated with PAH.24Batton K.A. Austin C.O. Bruno K.A. Burger C.D. Shapiro B.P. Fairweather D. Sex differences in pulmonary arterial hypertension: role of infection and autoimmunity in the pathogenesis of disease.Biol Sex Differ. 2018; 9: 15Crossref PubMed Scopus (36) Google Scholar Emerging research strongly suggests that nonhormonal factors such as sex chromosomes and sex bias in gene expression may also lead to sex-based differences in PAH penetrance and progression. Mammals have two distinct heteromorphic chromosomes that govern sex determination: the Y chromosome that contains few genes, approximately 70, present only in males; and the X chromosome containing between 900 and 1500 genes, present in two copies in female and one copy in male.25Migeon B.R. X-linked diseases: susceptible females.Genet Med. 2020; 22: 1156-1174Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar,26Snell D.M. 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This review highlights new findings related to how the sex chromosome complement and sex-differentiated epigenetic mechanisms to control gene expression are decisive players in the sexual dimorphism of PAH. The complex pathogenesis of PAH is not well understood. As a general agreement, genetic, environmental, and local factors are modifiers of vascular structure-function involved in the initiation, propagation, therapeutic response, and ultimate outcomes of the disease. A plethora of genomic mechanisms are increasingly recognized to participate in the pathogenesis of PAH. This article aims to outline new developments in the genomics of sexual dimorphism of PAH; for other facets of the disease, recent excellent reviews are available.32Luna R.C.P. de Oliveira Y. Lisboa J.V.C. Chaves T.R. de Araujo T.A.M. de Sousa E.E. Miranda Neto M. Pirola L. Braga V.A. de Brito Alves J.L. 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Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension.Nat Genet. 2000; 26: 81-84Crossref PubMed Scopus (1189) Google Scholar with the bone morphogenetic protein receptor 2 (BMPR2) gene encoding a receptor in the transforming growth factor-β superfamily, being the most mutated. More than 380 different BMPR2 mutations are found in about 70% of heritable PAH and 10% to 40% of idiopathic PAH cases.36Thomson J.R. Machado R.D. Pauciulo M.W. Morgan N.V. Humbert M. Elliott G.C. Ward K. Yacoub M. Mikhail G. Rogers P. Newman J. Wheeler L. Higenbottam T. Gibbs J.S. Egan J. Crozier A. Peacock A. Allcock R. Corris P. Loyd J.E. Trembath R.C. Nichols W.C. 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The authors hypothesize that pathogenesis of female PAH patients is more complicated, and the influence of BMPR2 mutations may be modified by other unknown factors (ie, critical molecules in the BMPR2 signaling pathways, level of BMPR2 expression, and sex hormones), making disparities in the prognosis between female mutation carriers and noncarriers less evident. The development of high-throughput sequencing approaches led to novel causal genes and additional pathways involved in PAH susceptibilities, such as pathogenic or likely pathogenic genetic variants in potassium channels [potassium two pore domain channel subfamily K 3, ATP binding cassette subfamily C member 8, and transcription factors (T-box transcription factor 4 and SRY-box transcription factor 17)].40Liu B. Zhu L. Yuan P. Marsboom G. Hong Z. Liu J. Zhang P. Hu Q. 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Besides genetic mutations, the changes in gene expression that occur without alteration of the DNA sequence may contribute to pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cell proliferation and vascular remodeling in PAH. DNA methylation, histone modification, and noncoding RNAs, able to turn the genes off and on, have been associated with PAH pathophysiology. DNA methylation analysis identified genes involved in lipid transport pathway, actin cytoskeletal rearrangements, cell migration, and proliferation, which could be relevant to PAH pathophysiology.47Hautefort A. Chesne J. Preussner J. Pullamsetti S.S. Tost J. Looso M. Antigny F. Girerd B. Riou M. Eddahibi S. Deleuze J.F. Seeger W. Fadel E. Simonneau G. Montani D. Humbert M. Perros F. Pulmonary endothelial cell DNA methylation signature in pulmonary arterial hypertension.Oncotarget. 2017; 8: 52995-53016Crossref PubMed Google Scholar,48Wang Y. Huang X. Leng D. Li J. Wang L. Liang Y. Wang J. Miao R. 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