Plasma 12‐ and 15‐Hydroxyeicosanoids are Predictors of Survival in Pulmonary Arterial Hypertension

Abstract

This study aimed to characterize alterations in select eicosanoids in experimental and human pulmonary arterial hypertension (PAH) and to assess their potential utility as predictors of outcome. Using liquid chromatography-mass spectrometry, we performed targeted lipidomic analyses of the lungs and right ventricles (RVs) of chronically hypoxic rats and plasma of consecutive PAH patients and healthy controls. In rat lungs, chronic hypoxia was associated with significantly decreased lung prostacyclin (PGI 2 )/thromboxane B 2 (TXB 2 ) ratio and elevated lung 8-hydroxyeicosanoid (HETE) acid concentrations. RV eicosanoids did not exhibit any changes with chronic hypoxia. PAH treatment-naïve patients had significantly increased plasma concentrations of TXB 2 and 5-, 8-, 12-, and 15-HETE. The PGI 2 /TXB 2 ratio was lower in PAH patients than in controls, especially in the treatment-naïve cohort (median: 2.1, 0.3, and 1.3 in controls, treatment-naïve, and treated patients, respectively, P = 0.001). Survival was significantly worse in PAH patients with 12-HETE high (≥57 pg/mL) and 15-HETE high (≥256 pg/mL) in unadjusted and adjusted analyses (hazard ratio [HR]: 2.8 [95% confidence interval (CI): 1.1-7.3], P = 0.04 and HR: 4.3 [95% CI: 1.6-11.8], P = 0.004, respectively; adjustment was performed with the REVEAL [Registry to Evaluate Early and Long-Term PAH Disease Management] risk score). We demonstrate significant alterations in eicosanoid pathways in experimental and human PAH. We found that 12-and 15-HETE were independent predictors of survival in human PAH, even after adjusting for the REVEAL score, suggesting their potential role as novel biomarkers.

Severe pulmonary hypertension in aging female apolipoprotein E-deficient mice is rescued by estrogen replacement therapy

“…Treatment of male ApoE-deficient mice with rosiglitazone (a PPARγ agonist) resulted in higher plasma adiponectin levels and a complete regression of PH [ 10 ]. Recent studies from our lab and others have implicated the involvement of oxidized lipids in the development and progression of PH [ 12 – 14 , 42 – 44 ]. Hemnes et al recently provided evidence for RV lipotoxicity in heritable PAH [ 45 ].…”

Arterial stiffness induces remodeling phenotypes in pulmonary artery smooth muscle cells via YAP/TAZ-mediated repression of cyclooxygenase-2

“…matrix stiffness; pulmonary hypertension; YAP/TAZ; COX-2; prostaglandins PULMONARY HYPERTENSION (PH) is characterized by progressive pulmonary vascular remodeling that leads to exertional shortness of breath, severe hypoxemia, and ultimately to right heart failure and death (54). Changes in prostaglandin activity have been shown to impact disease survival (2), and exogenous prostanoid therapy has been the cornerstone of treatment in severe disease for over 20 yr (66). Despite our increasing molecular and genetic understanding of the disease over this time frame, state-of-the-art therapies currently provide only modest improvements in quality of life, and new treatment modalities are urgently needed (18,74).…”

Bidirectional Control of Coronary Vascular Resistance by Eicosanoids via a Novel GPCR

“…Higher levels have been measured in serum (36-38). Importantly, 15-HETE levels are increased in patients with chronic in ammatory conditions (39) and vascular diseases, including coronary artery disease (40) and pulmonary arterial hypertension (41,42). Similarly, the concentration of EETs in plasma from healthy volunteers was reported to be in the low nanomolar range (median of 0.6 nM), with coronary artery disease (CAD) patients having higher EETs (median 1 nM) (43).…”