Abstract 11902: Nf-κB Controls Eicosanoid Production In Severe Angioproliferative Pulmonary Hypertension
Inflammation and an imbalance of immune responses are now recognized characteristics of many forms of severe pulmonary arterial hypertension (PAH). The Sugen5416/chronic hypoxia (SuHx) rat model is a model of severe angioproliferative PAH, which like the human condition displays plexiform like lesions and right ventricular failure. Both in human and in animal PAH the nature of the inflammatory response is not well understood and whether inflammation mechanistically contributes to the angioproliferation and PAH development remains unclear. We hypothesized that eicosanoid metabolites and the expression of the enzymes cPLA2, 5-LO and COX-2 are increased in the lung tissue from the SuHx pulmonary hypertensive animals. We also hypothesized that the expression of the genes encoding these enzyme proteins is transcriptional controlled by NF-κB. Sprague Dawley rats were injected with SU5416 s.c. at day 0 and exposed to chronic hypoxia. Some of the animals received 100 mg/kg of the NF-κB/proteasome-inhibitor pyrrolidine dithiocarbamate (PDTC) or vehicle daily from day 0-21. At day 21, animals underwent invasive hemodynamic measurements and lung tissue was harvested for histology and protein expression studies. Western blot and mass spectroscopy were used to determine the level of the arachidonic acid enzyme proteins and lipid metabolites in the lungs of SuHx rats. cPLA2, 5-LO and COX-2 protein expression was elevated in the SuHx rat lungs and reduced after PDTC treatment. Mass spectroscopy showed an increase of PGF2α, PGE2, TXB2, 6kPGF1α (products of the cyclooxygenase pathway) as well as 11HETE, 12 HETE and 15 HETE (products of lipoxygenase pathways) in the lung tissue homogenates of SuHx animals. We conclude, because PDTC treatment reduced NF-κB activity and prevented pulmonary angiobliteration, that NF-κB-dependent mechanisms contribute to the development of severe PAH in this model. Arachidonic acid enzyme proteins and eicosanoid metabolites are highly expressed in the SuHx rat lungs and the expression of the enzymes is controlled by NF-κB. Whether arachidonic acid enzymes or eicosanoids contribute to angioproliferation and whether inhibition of these enzymes and metabolites may be a useful strategy for the treatment of PAH remains to be investigated.
- © 2012 by American Heart Association, Inc.