Functional Impact of Human Genetic Variants of COL18A1/Endostatin on Pulmonary Endothelium.

Pulmonary arterial hypertension (PAH) is an incurable disease characterized by disordered and dysfunctional angiogenesis leading to small-vessel loss and an obliterative vasculopathy. The pathogenesis of PAH is not fully understood, but multiple studies have demonstrated links between elevated angiostatic factors, disease severity, and adverse clinical outcomes. ES (endostatin), one such circulating angiostatic peptide, is the cleavage product of the proteoglycan COL18A1 (collagen α1[XVIII] chain). Elevated serum ES is associated with increased mortality and disease severity in PAH. A nonsynonymous variant of ES (aspartic acid-to-asparagine substitution at amino acid 104; p.D104N) is associated with differences in PAH survival. Although COL18A1/ES expression is markedly increased in remodeled pulmonary vessels in PAH, the impact of ES on pulmonary endothelial cell (PEC) biology and molecular contributions to PAH severity remain undetermined. In the present study, we characterized the effects of exogenous ES on human PEC biology and signaling. We demonstrated that ES inhibits PEC migration, proliferation, and cell survival, with significant differences between human variants, indicating that they are functional genetic variants. ES promotes proteasome-mediated degradation of the transcriptional repressor ID1, increasing expression and release of TSP-1 (thrombospondin 1). ES inhibits PEC migration via an ID1/TSP-1/CD36-dependent pathway, in contrast to proliferation and apoptosis, which require both CD36 and CD47. Collectively, the data implicate ES as a novel negative regulator of ID1 and an upstream propagator of an angiostatic signal cascade converging on CD36 and CD47, providing insight into the cellular and molecular effects of a functional genetic variant linked to altered outcomes in PAH.

Efficacy and determinants of response to inhaled treprostinil in pulmonary hypertension - interstitial lung disease.

Inhaled treprostinil has shown to improve exercise capacity in patients with pulmonary hypertension-interstitial lung disease (PH-ILD). We evaluated the efficacy and determinants of favorable response to inhaled treprostinil at six months. METHODS: Of the 106 patients screened, 42 were eligible for this retrospective single-center study. Assessments included rate of patients who achieved ≥30m improvement on 6-min walk test (6MWT), and death or transplantation rates at 6 months of treatment initiation. RESULTS: Patients were predominantly female (n = 26, 62 %) with autoimmune PH-ILD (n = 23, 55 %), and a median age of 68 (61, 75) years. Ten (38.5 %) patients achieved a distance increase ≥30 m in 6MWT. No statistically significant determinants of walking ≥30 m were noted on univariate analysis; however, responders had a lower right ventricular (RV) tissue Doppler S' velocity (9.2 [7.0, 11.0] vs. 11.9 [10.0, 14.4], p = 0.018) cm/s and evidence of pericardial effusion on baseline echocardiogram (82 % vs. 26 %, p = 0.003). PH-ILD patients who died or underwent transplantation were more likely to have progressive pulmonary fibrosis (PPF) (95 % vs 50 %, p < 0.001) CONCLUSIONS: In real-world setting, treatment with inhaled treprostinil for six months increased the 6MWT by ≥ 30 m in about a third of PH-ILD patients. Lower RV tissue Doppler S' velocity and presence of pericardial effusion at baseline were associated with favorable response to inhaled treprostinil. PPF portends a poor survival in PH-ILD.