Endothelial Chromosome 13 Deletion in Congenital Heart Disease–associated Pulmonary Arterial Hypertension Dysregulates <i>SMAD9</i> Signaling

Drake, Kylie M.; Comhair, Suzy; Erzurum, Serpil C.; Tuder, Rubin M.; Aldred, Micheala A.

doi:10.1164/rccm.201411-1985le

Cited by 18 publications

(21 citation statements)

References 24 publications

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“…In support of this, our previous studies, which included some of the PAEC now found to harbor chromosome abnormalities, showed that PAH PAEC are hyperproliferative and resistant to apoptosis (13,55). In one case, we were able to show directly that a large interstitial deletion of chromosome 13 in PAEC conferred increased proliferation rate and altered bone morphogenetic protein signaling in comparison with chromosomally normal PASMC from the same lung (13).…”

Section: Original Articlesupporting

confidence: 70%

“…Table 1). This series includes the 10 cases and 8 control subjects we published previously (12,13). In PASMC the frequency of abnormalities was not significantly different between patients (5 of 28; 17.9%) and control cells (one of eight; 12.5%).…”

Section: Statisticsmentioning

confidence: 88%

“…Subsequently, we identified largescale cytogenetic abnormalities in a small series of pulmonary artery endothelial cells (PAEC) isolated from the explant lungs of patients with PAH (12). These abnormalities were also detectable in the uncultured lung tissue by fluorescent in situ hybridization (12,13), confirming they are not culture artifacts and suggesting there may be a higher rate of DNA damage and/or mitotic segregation errors in PAH lungs. Increased DNA damage has been identified in PAH lung vascular cells (14)(15)(16).…”

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confidence: 89%

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Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension

Federici¹,

Drake²,

Rigelsky³

et al. 2015

Am J Respir Crit Care Med

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Rationale: Pulmonary arterial hypertension (PAH) is a serious lung condition characterized by vascular remodeling in the precapillary pulmonary arterioles. We and others have demonstrated chromosomal abnormalities and increased DNA damage in PAH lung vascular cells, but their timing and role in disease pathogenesis is unknown.Objectives: We hypothesized that if DNA damage predates PAH, it might be an intrinsic cell property that is present outside the diseased lung.Methods: We measured DNA damage, mutagen sensitivity, and reactive oxygen species (ROS) in lung and blood cells from patients with Group 1 PAH, their relatives, and unrelated control subjects.Measurements and Main Results: Baseline DNA damage was significantly elevated in PAH, both in pulmonary artery endothelial cells (P , 0.05) and peripheral blood mononuclear cells (PBMC) (P , 0.001). Remarkably, PBMC from unaffected relatives showed similar increases, indicating this is not related to PAH treatments. ROS levels were also higher (P , 0.01). DNA damage correlated with ROS production and was suppressed by antioxidants (P , 0.001). PBMC from patients and relatives also showed markedly increased sensitivity to two chemotherapeutic drugs, bleomycin and etoposide (P , 0.001). Results were consistent across idiopathic, heritable, and associated PAH groups.Conclusions: Levels of baseline and mutagen-induced DNA damage are intrinsically higher in PAH cells. Similar results in PBMC from unaffected relatives suggest this may be a genetically determined trait that predates disease onset and may act as a risk factor contributing to lung vascular remodeling following endothelial cell injury. Further studies are required to fully characterize mutagen sensitivity, which could have important implications for clinical management.

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Section: Original Articlesupporting

confidence: 70%

Section: Statisticsmentioning

confidence: 88%

mentioning

confidence: 89%

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Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension

Federici¹,

Drake²,

Rigelsky³

et al. 2015

Am J Respir Crit Care Med

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“…Yet, paradoxically, rare patients present with a combined HHT/PAH syndrome [218]. From a genetic standpoint, the relationship makes some sense: heterozygous mutations in BMPR2 , which encodes a type II receptor that can partner with ALK1, account for more than 70% of heritable PAH and up to 20% of the more common idiopathic PAH [219, 220], and causal mutations in SMAD9 (which encodes SMAD8), which signals downstream of ALK1, have also been reported [221, 222]. Most commonly, patients who present with HHT/PAH harbor heterozygous mutations in ACVRL1 , or less often, BMPR2 [218, 223–226].…”

Section: Emerging Roles For Alk1 Signalingmentioning

confidence: 99%

ALK1 signaling in development and disease: new paradigms

Roman

Hinck

2017

Cell. Mol. Life Sci.

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Activin A receptor like type 1 (ALK1) is a transmembrane serine/threonine receptor kinase in the transforming growth factor-beta receptor family that is expressed on endothelial cells. Defects in ALK1 signaling cause the autosomal dominant vascular disorder, hereditary hemorrhagic telangiectasia (HHT), which is characterized by development of direct connections between arteries and veins, or arteriovenous malformations (AVMs). Although previous studies have implicated ALK1 in various aspects of sprouting angiogenesis, including tip/stalk cell selection, migration, and proliferation, recent work suggests an intriguing role for ALK1 in transducing a flow-based signal that governs directed endothelial cell migration within patent, perfused vessels. In this review, we present an updated view of the mechanism of ALK1 signaling, put forth a unified hypothesis to explain the cellular missteps that lead to AVMs associated with ALK1 deficiency, and discuss emerging roles for ALK1 signaling in diseases beyond HHT.

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“…A number of groups are working on these issues, for instance, by delivering the gene-editing components through viruses (71). This could also hold promise for the targeted correction of somatic lung cells with spontaneous mutations due to increased mutagen sensitivity, which may be a feature of PAH (72)(73)(74). The use of gene editing has yet to reach the bedside, but this rapidly evolving field may provide great opportunities for therapeutic approaches in the near future.…”

Section: C/fpomentioning

confidence: 99%