Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities.
Pulmonary arterial hypertension (PAH) is a proliferative vasculopathy characterized by high circulating CD34(+)CD133(+) proangiogenic progenitors, and endothelial cells that have pathologic expression of hypoxia-inducible factor 1 α (HIF-1α). Here, CD34(+)CD133(+) progenitor cell numbers are shown to be higher in PAH bone marrow, blood, and pulmonary arteries than in healthy controls. The HIF-inducible myeloid-activating factors erythropoietin, stem cell factor (SCF), and hepatocyte growth factor (HGF) are also present at higher than normal levels in PAH blood, and related to disease severity. Primary endothelial cells harvested from human PAH lungs produce greater HGF and progenitor recruitment factor stromal-derived factor 1 α (SDF-1α) than control lung endothelial cells, and thus may contribute to bone marrow activation. Even though PAH patients had normal numbers of circulating blood elements, hematopoietic alterations in myeloid and erythroid lineages and reticulin fibrosis identified a subclinical myeloproliferative process. Unexpectedly, evaluation of bone marrow progenitors and reticulin in nonaffected family members of patients with familial PAH revealed similar myeloid abnormalities. Altogether, the results show that PAH is linked to myeloid abnormalities, some of which may be related to increased production of HIF-inducible factors by diseased pulmonary vasculature, but findings in nonaffected family suggest myeloid abnormalities may be intrinsic to the disease process.
Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. farhas@ccf.org
Samar
S
Farha
Kewal
K
Asosingh
Weiling
W
Xu
Jacqueline
J
Sharp
Deepa
D
George
Suzy
S
Comhair
Margaret
M
Park
W H Wilson
WH
Tang
James E
JE
Loyd
Karl
K
Theil
Raymond
R
Tubbs
Eric
E
Hsi
Alan
A
Lichtin
Serpil C
SC
Erzurum
D000071916:AC133 Antigen; D000328:Adult; D015703:Antigens, CD / Q000097:blood / Q000378:metabolism; D018952:Antigens, CD34 / Q000097:blood / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism / Q000502:physiology*; D001855:Bone Marrow Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D002478:Cells, Cultured; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006023:Glycoproteins / Q000097:blood / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia / Q000097:blood / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000097:blood / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D051792:Basic Helix-Loop-Helix Proteins; D006023:Glycoproteins; D051793:Hypoxia-Inducible Factor 1; D010455:Peptides; C000606023:PROM1 protein, human
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