Proteomic identification of altered apolipoprotein patterns in pulmonary hypertension and vasculopathy of sickle cell disease.
Pulmonary arterial hypertension (PAH) is emerging as a major complication and independent risk factor for death among adults with sickle cell disease (SCD). Using surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS), we searched for biomarkers of PAH in plasma specimens from 27 homozygous sickle cell anemia (HbSS) patients with PAH and 28 without PAH. In PAH patients, analysis consistently showed lower abundance of a 28.1-kDa peak (P < .001), identified by high-resolution mass spectrometry as the oxidant-scavenging protein apolipoprotein A-I (apoA-I), which correlated with clinical assays of apoA-I (r = .58, P < .001) and high-density lipoprotein (HDL) levels (r = .50, P = .001). Consistent with endothelial dysfunction that may mediate this effect in PAH, HbSS patients with lower apoA-I levels also displayed impaired vasodilatory responses to acetylcholine (mean +/- SEM, 189% +/- 34% [n = 13] vs 339% +/- 51% [n = 13], P < .001). As a group, patients with SCD demonstrated significantly lower apoA-I levels than African-American control subjects. The PAH cohort was further characterized by high levels of apolipoproteins A-II and B and serum amyloid A, and low levels of haptoglobin dimers and plasminogen. These results imply a relationship of apolipoproteins to the development of PAH vasculopathy in SCD, potentially involving an unexpected mechanistic parallel to atherosclerosis, another proliferative vasculopathy.
Yuditskaya
Susan
S
Pulmonary and Vascular Medicine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1476, USA.
Tumblin
Ashaunta
A
Hoehn
Gerard T
GT
Wang
Guanghui
G
Drake
Steven K
SK
Xu
Xiuli
X
Ying
Saixia
S
Chi
Amy H
AH
Remaley
Alan T
AT
Shen
Rong-Fong
RF
Munson
Peter J
PJ
Suffredini
Anthony F
AF
Kato
Gregory J
GJ
D000328:Adult; D001741:Black or African American; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000150:complications; D001053:Apolipoproteins / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood* / Q000209:etiology; D008297:Male; D040901:Proteomics; D012307:Risk Factors; D000685:Serum Amyloid A Protein / Q000378:metabolism*
D001053:Apolipoproteins; D015415:Biomarkers; D000685:Serum Amyloid A Protein