title: Proinflammatory high-density lipoprotein results from oxidized lipid mediators in the pathogenesis of both idiopathic and associated types of pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) is characterized by abnormal elaboration of vasoactive peptides, endothelial cell dysfunction, vascular remodeling, and inflammation, which collectively contribute to its pathogenesis. We investigated the potential for high-density lipoprotein (HDL) dysfunction (i.e., proinflammatory effects) and abnormal plasma eicosanoid levels to contribute to the pathobiology of PAH and assessed ex vivo the effect of treatment with apolipoprotein A-I mimetic peptide 4F on the observed HDL dysfunction. We determined the "inflammatory indices" HII and LII for HDL and low-density lipoprotein (LDL), respectively, in subjects with idiopathic PAH (IPAH) and associated PAH (APAH) by an in vitro monocyte chemotaxis assay. The 4F was added ex vivo, and repeat LII and HII values were obtained versus a sham treatment. We further determined eicosanoid levels in plasma and HDL fractions from patients with IPAH and APAH relative to controls. The LIIs were significantly higher for IPAH and APAH patients than for controls. Incubation of plasma with 4F before isolation of LDL and HDL significantly reduced the LII values, compared with sham-treated LDL, for IPAH and APAH. The increased LII values reflected increased states of LDL oxidation and thereby increased proinflammatory effects in both cohorts. The HIIs for both PAH cohorts reflected a "dysfunctional HDL phenotype," that is, proinflammatory HDL effects. In contrast to "normal HDL function," the determined HIIs were significantly increased for the IPAH and APAH cohorts. Ex vivo 4F treatment significantly improved the HDL function versus the sham treatment. Although there was a significant "salutary effect" of 4F treatment, this did not entirely normalize the HII. Significantly increased levels for both IPAH and APAH versus controls were evident for the eicosanoids 9-HODE, 13-HODE, 5-HETE, 12-HETE, and 15-HETE, while no statistical differences were evident for comparisons of IPAH and APAH for the determined plasma eicosanoid levels in the HDL fractions. Our study has further implicated the putative role of "oxidant stress" and inflammation in the pathobiology of PAH. Our data suggest the influences on the "dysfunctional HDL phenotype" of increased oxidized fatty acids, which are paradoxically proinflammatory. We speculate that therapies that target either the "inflammatory milieu" or the "dysfunctional HDL phenotype," such as apoA-I mimetic peptides, may be valuable avenues of further research in pulmonary vascular diseases.
authors.affiliation: Division of Pulmonary, Critical Care, Allergy, and Immunology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Ross
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Hough
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Hama
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Jamil
authors.initials: J
authors.lastname: Aboulhosn
authors.affiliation: Division of Pulmonary, Critical Care, Allergy, and Immunology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Belperio
authors.affiliation: Division of Pulmonary, Critical Care, Allergy, and Immunology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Rajan
authors.initials: R
authors.lastname: Saggar
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Van Lenten
authors.affiliation: Division of Cardiothoracic Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Abbas
authors.initials: A
authors.lastname: Ardehali
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Eghbali
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Reddy
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Fogelman
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Navab
keywords: high-density lipoprotein; hydroxyeicosatetraenoic acids; hydroxyoctadecadienoic acids; inflammatory index; low-density lipoprotein; pulmonary arterial endothelial cells; pulmonary arterial hypertension; pulmonary arterial smooth muscle cells