Inhibition of Obesity-Induced Pulmonary Arterial Hypertension by Electrophilic Fatty Acids

GOR S; KELLEY EE; BAUST J; BONACCI G; GOLIN-BISELLO F; CANTU-MEDELLIN N; DEVLIN JE; ST CROIX CM; WATKINS SC; CHAMPION HC; FREEMAN BA; KHOO NKH

San Diego

Congreso; 19th Annual Meeting of the Society for Free Radical Biology and Medicine; 2012

Society for Free Radical Biology and Medicine (SFRBM)

Obesity is now being recognized as a risk factor for pulmonary arterial hypertension (PAH), a disease with poor prognosis for survival. Remodeling of small pulmonary arteries in PAH increases pulmonary vascular resistance (PVR) and right ventricular failure. Multiple inflammatory mediators, including increased rates of reactive species production in the vasculature contribute to the pathogenesis of PAH. The endogenous electrophilic fatty acid nitroalkene derivative, 9- and 10-nitrooctadec-9-enoic acid (nitro-oleic acid, OA-NO2) was administered at nM concentrations in a murine model of obesity-induced PAH. C57BL/6j male mice fed a high fat diet (HFD, 60% kcal from fat) for 20 wk had increased right ventricular end systolic pressure (RVESP, 37.7 ± 3.4 mmHg), pulmonary vascular resistance (PVR, 1.3 ± 0.13 mmHg/ml/min) and diastolic function (6.7 ± 0.7ms, Tau) compared to normal chow controls. OA-NO2 treatment for the final 6.5 wk of a 20 wk HFD significantly decreased RVESP (24.7 ± 1.1 mm Hg), PVR (0.76 ± 0.05), Tau (4 ± 0.4 ms) and right ventricular hypertrophy. Macrophage infiltration, pulmonary artery wall α-smooth muscle actin expression and a source of pro-inflammatory oxidants, xanthine oxidoreductase (XOR), were also suppressed by OA-NO2. Electrophilic fatty acid administration potently inhibited pulmonary hypertension and vascular remodeling in this model of obesity-induced PAH and can represent a new therapeutic modality.