TY - JOUR
T1 - Insulin-like growth factor binding protein-2
T2 - A new circulating indicator of pulmonary arterial hypertension severity and survival
AU - Yang, Jun
AU - Griffiths, Megan
AU - Nies, Melanie K.
AU - Brandal, Stephanie
AU - Damico, Rachel
AU - Vaidya, Dhananjay
AU - Tao, Xueting
AU - Simpson, Catherine E.
AU - Kolb, Todd M.
AU - Mathai, Stephen C.
AU - Pauciulo, Michael W.
AU - Nichols, William C.
AU - Ivy, David D.
AU - Austin, Eric D.
AU - Hassoun, Paul M.
AU - Everett, Allen D.
N1 - Publisher Copyright:
© 2020 The Author(s).
PY - 2020/10/6
Y1 - 2020/10/6
N2 - Background: Pulmonary arterial hypertension (PAH) is a fatal disease that results from cardio-pulmonary dysfunction with the pathology largely unknown. Insulin-like growth factor binding protein 2 (IGFBP2) is an important member of the insulin-like growth factor family, with evidence suggesting elevation in PAH patients. We investigated the diagnostic and prognostic value of serum IGFBP2 in PAH to determine if it could discriminate PAH from healthy controls and if it was associated with disease severity and survival. Methods: Serum IGFBP2 levels, as well as IGF1/2 levels, were measured in two independent PAH cohorts, the Johns Hopkins Pulmonary Hypertension program (JHPH, N = 127), NHLBI PAHBiobank (PAHB, N = 203), and a healthy control cohort (N = 128). The protein levels in lung tissues were determined by western blot. The IGFBP2 mRNA expression levels in pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) were assessed by RNA-seq, secreted protein levels by ELISA. Association of biomarkers with clinical variables was evaluated using adjusted linear or logistic regression and Kaplan-Meier analysis. Results: In both PAH cohorts, serum IGFBP2 levels were significantly elevated (p < 0.0001) compared to controls and discriminated PAH from controls with an AUC of 0.76 (p < 0.0001). A higher IGFBP2 level was associated with a shorter 6-min walk distance (6MWD) in both cohorts after adjustment for age and sex (coefficient-50.235 and-57.336 respectively). Cox multivariable analysis demonstrated that higher serum IGFBP2 was a significant independent predictor of mortality in PAHB cohort only (HR, 3.92; 95% CI, 1.37-11.21). IGF1 levels were significantly increased only in the PAHB cohort; however, neither IGF1 nor IGF2 had equivalent levels of associations with clinical variables compared with IGFBP2. Western blotting shown that IGFBP2 protein was significantly increased in the PAH vs control lung tissues. Finally, IGFBP2 mRNA expression and secreted protein levels were significantly higher in PASMC than in PAEC. Conclusions: IGFBP2 protein expression was increased in the PAH lung, and secreted by PASMC. Elevated circulating IGFBP2 was associated with PAH severity and mortality and is a potentially valuable prognostic marker in PAH.
AB - Background: Pulmonary arterial hypertension (PAH) is a fatal disease that results from cardio-pulmonary dysfunction with the pathology largely unknown. Insulin-like growth factor binding protein 2 (IGFBP2) is an important member of the insulin-like growth factor family, with evidence suggesting elevation in PAH patients. We investigated the diagnostic and prognostic value of serum IGFBP2 in PAH to determine if it could discriminate PAH from healthy controls and if it was associated with disease severity and survival. Methods: Serum IGFBP2 levels, as well as IGF1/2 levels, were measured in two independent PAH cohorts, the Johns Hopkins Pulmonary Hypertension program (JHPH, N = 127), NHLBI PAHBiobank (PAHB, N = 203), and a healthy control cohort (N = 128). The protein levels in lung tissues were determined by western blot. The IGFBP2 mRNA expression levels in pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) were assessed by RNA-seq, secreted protein levels by ELISA. Association of biomarkers with clinical variables was evaluated using adjusted linear or logistic regression and Kaplan-Meier analysis. Results: In both PAH cohorts, serum IGFBP2 levels were significantly elevated (p < 0.0001) compared to controls and discriminated PAH from controls with an AUC of 0.76 (p < 0.0001). A higher IGFBP2 level was associated with a shorter 6-min walk distance (6MWD) in both cohorts after adjustment for age and sex (coefficient-50.235 and-57.336 respectively). Cox multivariable analysis demonstrated that higher serum IGFBP2 was a significant independent predictor of mortality in PAHB cohort only (HR, 3.92; 95% CI, 1.37-11.21). IGF1 levels were significantly increased only in the PAHB cohort; however, neither IGF1 nor IGF2 had equivalent levels of associations with clinical variables compared with IGFBP2. Western blotting shown that IGFBP2 protein was significantly increased in the PAH vs control lung tissues. Finally, IGFBP2 mRNA expression and secreted protein levels were significantly higher in PASMC than in PAEC. Conclusions: IGFBP2 protein expression was increased in the PAH lung, and secreted by PASMC. Elevated circulating IGFBP2 was associated with PAH severity and mortality and is a potentially valuable prognostic marker in PAH.
KW - Biomarker
KW - Insulin-like growth factor binding protein 2
KW - Pulmonary arterial hypertension
KW - Survival
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U2 - 10.1186/s12916-020-01734-3
DO - 10.1186/s12916-020-01734-3
M3 - Article
C2 - 33019943
AN - SCOPUS:85092323853
SN - 1741-7015
VL - 18
JO - BMC medicine
JF - BMC medicine
IS - 1
M1 - 268
ER -