Increased Mutagen Sensitivity and DNA Damage in Pulmonary Arterial Hypertension.
BACKGROUND
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.


OBJECTIVE
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.


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.
1 Genomic Medicine Institute and.
Chiara
C
Federici
1 Genomic Medicine Institute and.
Kylie M
http://orcid.org/0000-0003-1405-4694
KM
Drake
1 Genomic Medicine Institute and.
Christina M
CM
Rigelsky
1 Genomic Medicine Institute and.
Lauren N
LN
McNelly
1 Genomic Medicine Institute and.
Sirena L
SL
Meade
2 Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
Suzy A A
SA
Comhair
2 Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
Serpil C
SC
Erzurum
1 Genomic Medicine Institute and.
Micheala A
http://orcid.org/0000-0002-7390-9181
MA
Aldred
D002869:Chromosome Aberrations; D004249:DNA Damage / Q000235:genetics*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D011651:Pulmonary Artery / Q000473:pathology; D017382:Reactive Oxygen Species / Q000097:blood
D017382:Reactive Oxygen Species
BMPR2; DNA damage; genetic susceptibility; reactive oxygen species