TY - JOUR
T1 - Collagen 18A1/Endostatin Expression in the Progression of Right Ventricular Remodeling and Dysfunction in Pulmonary Arterial Hypertension
AU - Ambade, Anjira S.
AU - Naranjo, Mario
AU - Tuhy, Tijana
AU - Yu, Rose
AU - Marimoutou, Mery
AU - Everett, Allen
AU - Shimoda, Larissa A.
AU - Zimmerman, Stefan
AU - Cubero Salazar, Ilton M.
AU - Simpson, Catherine
AU - Tedford, Ryan J.
AU - Hsu, Steven
AU - Hassoun, Paul
AU - Damico, Rachel
N1 - Publisher Copyright:
© 2024 by the American Thoracic Society.
PY - 2024/9/1
Y1 - 2024/9/1
N2 - Numerous studies have demonstrated that endostatin (ES), a potent angiostatic peptide derived from collagen type XVIII a 1 chain and encoded by COL18A1, is elevated in pulmonary arterial hypertension (PAH). It is important to note that elevated ES has consistently been associated with altered hemodynamics, poor functional status, and adverse outcomes in adult and pediatric PAH. This study used serum samples from patients with Group I PAH and plasma and tissue samples derived from the Sugen/hypoxia rat pulmonary hypertension model to define associations between COL18A1/ES and disease development, including hemodynamics, right ventricle (RV) remodeling, and RV dysfunction. Using cardiac magnetic resonance imaging and advanced hemodynamic assessments with pressure–volume loops in patients with PAH to assess RV–pulmonary arterial coupling, we observed a strong relationship between circulating ES levels and metrics of RV structure and function. Specifically, RV mass and the ventricular mass index were positively associated with ES, whereas RV ejection fraction and RV–pulmonary arterial coupling were inversely associated with ES levels. Our animal data demonstrate that the development of pulmonary hypertension is associated with increased COL18A1/ES in the heart as well as the lungs. Disease-associated increases in COL18A1 mRNA and protein were most pronounced in the RV compared with the left ventricle and lung. COL18A1 expression in the RV was strongly associated with disease-associated changes in RV mass, fibrosis, and myocardial capillary density. These findings indicate that COL18A1/ES increases early in disease development in the RV and implicates COL18A1/ES in pathologic RV dysfunction in PAH.
AB - Numerous studies have demonstrated that endostatin (ES), a potent angiostatic peptide derived from collagen type XVIII a 1 chain and encoded by COL18A1, is elevated in pulmonary arterial hypertension (PAH). It is important to note that elevated ES has consistently been associated with altered hemodynamics, poor functional status, and adverse outcomes in adult and pediatric PAH. This study used serum samples from patients with Group I PAH and plasma and tissue samples derived from the Sugen/hypoxia rat pulmonary hypertension model to define associations between COL18A1/ES and disease development, including hemodynamics, right ventricle (RV) remodeling, and RV dysfunction. Using cardiac magnetic resonance imaging and advanced hemodynamic assessments with pressure–volume loops in patients with PAH to assess RV–pulmonary arterial coupling, we observed a strong relationship between circulating ES levels and metrics of RV structure and function. Specifically, RV mass and the ventricular mass index were positively associated with ES, whereas RV ejection fraction and RV–pulmonary arterial coupling were inversely associated with ES levels. Our animal data demonstrate that the development of pulmonary hypertension is associated with increased COL18A1/ES in the heart as well as the lungs. Disease-associated increases in COL18A1 mRNA and protein were most pronounced in the RV compared with the left ventricle and lung. COL18A1 expression in the RV was strongly associated with disease-associated changes in RV mass, fibrosis, and myocardial capillary density. These findings indicate that COL18A1/ES increases early in disease development in the RV and implicates COL18A1/ES in pathologic RV dysfunction in PAH.
KW - endostatin
KW - pulmonary arterial hypertension
KW - right heart
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UR - http://www.scopus.com/inward/citedby.url?scp=85202906526&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2024-0039OC
DO - 10.1165/rcmb.2024-0039OC
M3 - Article
C2 - 38861354
AN - SCOPUS:85202906526
SN - 1044-1549
VL - 71
SP - 343
EP - 355
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 3
ER -