title: Serotonylated fibronectin is elevated in pulmonary hypertension.
abstract: Serotonin (5-HT) and fibronectin (FN) have been associated with pulmonary hypertension (PH). We previously reported that FN is posttranslationally modified by tissue transglutaminase (TGase) to form serotonylated FN (s-FN) in pulmonary artery smooth muscle cells and that serotonylation stimulates their proliferation and migration, hallmarks of PH. We hypothesized that s-FN and its binding to TGase are elevated in human and experimental PH. To assess this hypothesis, FN isolation and electrophoretic, immunoblotting, and densitometric techniques were used. Mean ratio of serum s-FN to total FN level (s-FN/FN) was elevated in 19 consecutive pulmonary arterial hypertension (PAH) patients compared with 25 controls (0.3 ± 0.18 vs. 0.05 ± 0.07, P < 0.001). s-FN/FN also was increased in lungs of mice and rats with hypoxia-induced PH and in rats with monocrotaline-induced PH. In mice, the increase was detected at 1 wk of hypoxia, preceding the development of PH. Hypoxic rats had elevated serum s-FN/FN. Enhanced binding of TGase to its substrate FN occurred in serum from patients with PAH (mean 0.50 ± 0.51 vs. 0.063 ± 0.11, P = 0.002) and s-FN/FN and TGase-bound FN were highly correlated (R(2) = 0.77). TGase-bound FN also was increased in experimental PH. We conclude that increased serotonylation of FN occurs in human and experimental PH and may provide a biomarker for the disease.
authors.affiliation: Tufts University School of Medicine, Tufts Medical Center, Tupper Research Institute, Boston, MA 02111, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wei
authors.forename: Rod R
authors.initials: RR
authors.lastname: Warburton
authors.forename: Ioana R
authors.initials: IR
authors.lastname: Preston
authors.forename: Kari E
authors.initials: KE
authors.lastname: Roberts
authors.forename: Suzy A A
authors.initials: SA
authors.lastname: Comhair
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Hill
authors.forename: Barry L
authors.initials: BL
authors.lastname: Fanburg
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005353:Fibronectins / Q000097:blood / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D011503:Transglutaminases / Q000378:metabolism
chemical_list: D005353:Fibronectins; D012701:Serotonin; D011503:Transglutaminases