Anjira S. Ambade, Mario Naranjo, Tijana Tuhy, Rose Yu, Mery Marimoutou, Allen D. Everett, Larissa A. Shimoda, Stefean L. Zimmerman, Ilton M. Cubero Salazar, Catherine E. Simpson, Ryan J. Tedford, Steven Hsu, Paul M. Hassoun, Rachel L. Damico
Johns Hopkins University. Temple University. Johns Hopkins Community Physicians.
Institute for In Vitro Sciences Inc. Medical University of South Carolina.
United States
American Journal of Respiratory Cell and Molecular Biology
Am J Respir Cell Mol Biol 2024;
DOI: 10.1165/rcmb.2024-0039OC
Abstract
Numerous studies have demonstrated that endostatin (ES), a potent angiostatic peptide derived from collagen type XVIII alpha 1 chain and encoded by COL18A1, is elevated in pulmonary arterial hypertension (PAH). Importantly, 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/Chronic hypoxic (SuHx) rat pulmonary hypertension (PH) model to define associations between COL18A1/ES and disease development, including hemodynamics, right ventricular (RV) remodeling, and RV dysfunction. Using cardiac magnetic resonance (CMR) imaging and advanced hemodynamic assessments with pressure-volume (PV) loops in patients with PAH to assess RV-pulmonary arterial (PA) 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 (VMI) were positively associated with ES while RV ejection fraction and RV-PA coupling were inversely associated with ES levels. Our animal data demonstrates that the development of PH 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 to the left ventricle (LV) 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 increase early in disease development in the RV and implicate COL18A1/ES in pathologic RV dysfunction in PAH.
Category
Genetic Factors Associated with Pulmonary Vascular Disease
Potential Biomarkers Associated with Pulmonary Vascular Disease
Right Heart Dysfunction Associated with Pulmonary Vascular Disease
Diagnostic Testing for Pulmonary Vascular Disease. Non-invasive Testing
Animal Models of Pulmonary Vascular Disease and Therapy
Age Focus: Pediatric Pulmonary Vascular Disease or Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
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