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.