Osteopontin in Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a pathological condition with multifactorial etiology, which is characterized by elevated pulmonary arterial pressure and pulmonary vascular remodeling. The underlying pathogenetic mechanisms remain poorly understood. Accumulating clinical evidence suggests that circulating osteopontin may serve as a biomarker of PH progression, severity, and prognosis, as well as an indicator of maladaptive right ventricular remodeling and dysfunction. Moreover, preclinical studies in rodent models have implicated osteopontin in PH pathogenesis. Osteopontin modulates a plethora of cellular processes within the pulmonary vasculature, including cell proliferation, migration, apoptosis, extracellular matrix synthesis, and inflammation via binding to various receptors such as integrins and CD44. In this article, we provide a comprehensive overview of the current understanding of osteopontin regulation and its impact on pulmonary vascular remodeling, as well as consider research issues required for the development of therapeutics targeting osteopontin as a potential strategy for the management of PH.

Keywords: biomarkers; osteopontin; pulmonary hypertension; right heart failure.

Figure 1

Clinical role of osteopontin. In patients with pulmonary hypertension (PH) of various etiologies (1), changes to the pulmonary vessels and the right ventricle (RV) (2) cause enhanced osteopontin release into the bloodstream. Circulating osteopontin can be measured in plasma or serum samples (3). Numerous studies (4) have found that osteopontin levels are increased in PH patients, and these elevated levels are linked to invasive hemodynamic alterations, changes in the functional and structural parameters of the RV, and adverse outcomes. CHD-PAH, pulmonary artery hypertension associated with congenital heart disease; IPAH, idiopathic pulmonary artery hypertension; COPD, chronic obstructive pulmonary disease; DCM, dilated cardiomyopathy; CTD, connective tissue disease; CTEPH, chronic thromboembolic pulmonary hypertension; RA, right atrium.

Figure 2

Regulation of osteopontin expression and effects of osteopontin in pulmonary vascular cells. Several factors regulate osteopontin expression in pulmonary vascular cells. In adventitial fibroblasts, hypoxia induces osteopontin expression, which has implications in cell proliferation and migration. In pulmonary artery smooth muscle cells, many factors regulate osteopontin expression, including hypoxia, PDGF (platelet-derived growth factor), TGF-beta (transforming growth factor beta), FGF1 (fibroblast growth factor 1), Ang-II (angiotensin II), S1P (sphingosine 1-phosphate), and mechanical stress, all of which also regulate cell proliferation and migration. However, the exact factors regulating osteopontin in pulmonary vascular endothelial cells and macrophages have not been identified. While osteopontin regulates macrophage chemotaxis, its role in endothelial cells remains unknown.

Figure 3

Possible implications of experimental pulmonary hypertension models in future studies. (A) Among many available mouse and rat pulmonary hypertension models, listed here (hypoxia, shunt, monocrotaline, sugen plus hypoxia (SuHx), pulmonary artery banding (PAB)), osteopontin-targeted studies were performed only in hypoxia-exposed global osteopontin knockout mice and in a rat model of shunt-induced pulmonary hypertension using osteopontin receptor (αVβ3) antagonist. Osteopontin-oriented in vivo studies in other pulmonary hypertension models are still missing. There have been no studies with cell-specific osteopontin deletion or overexpression in rodent pulmonary hypertension models. —indicates that animal models with the corresponding osteopontin manipulations are available; NA—studies with the corresponding animal models and osteopontin manipulations are not available. (B) No experimental studies have evaluated effects of recombinant osteopontin application or osteopontin-neutralizing antibodies. In order to elucidate the cell specific roles of osteopontin, the Cre/LoxP system can be utilized using cell-specific promoter systems. Further, to better characterize the role of osteopontin in such models it is recommended to use invasive catheterization (C) to measure right atrial (RA) pressure, right ventricular (RV) systolic pressure (RVSP), RV diastolic pressure (RVDP), aortic pressure, left ventricular (LV) systolic pressure (LVSP) and LV diastolic pressure (LVDP). Echocardiographic imaging (D) of the heart is also warranted to inform additional characteristics of the RV including both systolic and diastolic functions, including the following parameters: the ratio of pulmonary artery acceleration time to pulmonary artery ejection time (PAAT/PAET), tricuspid annulus systolic excursion (TAPSE), RV annulus systolic velocity (RV-S´), RV internal diameter (RVID), RV wall thickness (RVWT), stroke volume (SV), cardiac output (CO), LV eccentricity index (LVEI), tricuspid valve inflow velocities (TV E/A), and tricuspid annulus lateral velocities (TV E´/A´). Following the terminal catheterization and echocardiography assessments, lung and heart tissues (E) can be evaluated ex vivo for pulmonary artery (PA) wall thickness, muscularization and inflammation, as well as lung capillary density. RV tissue can be assessed for RV fibrosis, cardiomyocyte hypertrophy, inflammation, and angiogenesis. Furthermore, lung and RV tissues can be studied for the expression of genes and proteins involved in various pathological processes including inflammation, extracellular matrix (ECM) synthesis and endothelial-to-mesenchymal transition (EndMT). Finally, the exact cellular roles of osteopontin can be studied in vitro (F) using cell culture techniques under both osteopontin loss- and gain-of-function conditions to assess cell proliferation, migration, and apoptosis. Employing such strategies in rodent pulmonary hypertension models, and ex vivo tissue and in vitro cell culture experiments may be necessary to fully characterize the role of osteopontin in pulmonary hypertension.