title: Obesity-related pulmonary arterial hypertension in rats correlates with increased circulating inflammatory cytokines and lipids and with oxidant damage in the arterial wall but not with hypoxia.
abstract: Obesity is causally linked to a number of comorbidities, including cardiovascular disease, diabetes, renal dysfunction, and cancer. Obesity has also been linked to pulmonary disorders, including pulmonary arterial hypertension (PAH). It was long believed that obesity-related PAH was the result of hypoventilation and hypoxia due to the increased mechanical load of excess body fat. However, in recent years it has been proposed that the metabolic and inflammatory disturbances of obesity may also play a role in the development of PAH. To determine whether PAH develops in obese rats in the absence of hypoxia, we assessed pulmonary hemodynamics and pulmonary artery (PA) structure in the diet-resistant/diet-induced obesity (DR/DIO) and Zucker lean/fatty rat models. We found that high-fat feeding (DR/DIO) or overfeeding (Zucker) elicited PA remodeling, neomuscularization of distal arterioles, and elevated PA pressure, accompanied by right ventricular (RV) hypertrophy. PA thickening and distal neomuscularization were also observed in DIO rats on a low-fat diet. No evidence of hypoventilation or chronic hypoxia was detected in either model, nor was there a correlation between blood glucose or insulin levels and PAH. However, circulating inflammatory cytokine levels were increased with high-fat feeding or calorie overload, and hyperlipidemia and oxidant damage in the PA wall correlated with PAH in the DR/DIO model. We conclude that hyperlipidemia and peripheral inflammation correlate with the development of PAH in obese subjects. Obesity-related inflammation may predispose to PAH even in the absence of hypoxia.
authors.affiliation: Division of Cardiovascular Pulmonary Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA ; Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA ; These authors contributed equally to this research.
authors.forename: David C
authors.initials: DC
authors.lastname: Irwin
authors.affiliation: Division of Cardiovascular Pulmonary Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA ; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA ; These authors contributed equally to this research.
authors.forename: Chrystelle V
authors.initials: CV
authors.lastname: Garat
authors.affiliation: Division of Cardiovascular Pulmonary Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA ; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Crossno
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA ; Colorado Obesity Research Initiative, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: MacLean
authors.affiliation: Division of Cardiovascular Pulmonary Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Sullivan
authors.affiliation: Division of Cardiovascular Pulmonary Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Erickson
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Jackman
authors.affiliation: Division of Cardiovascular Pulmonary Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Julie W
authors.initials: JW
authors.lastname: Harral
authors.affiliation: Division of Cardiovascular Pulmonary Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA ; Division of Endocrinology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Jane E B
authors.initials: JE
authors.lastname: Reusch
authors.affiliation: Division of Cardiovascular Pulmonary Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA ; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA ; Colorado Obesity Research Initiative, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Dwight J
authors.initials: DJ
authors.lastname: Klemm
keywords: hyperlipidemia; hypoxia; inflammation; insulin resistance; obesity; oxidant damage; pulmonary hypertension