Abstract 20623: HDL Mimetic Peptide 4F Prevents Western Diet-Induced Pulmonary Hypertension and Right Ventricular Dysfunction in LDL-Receptor Deficient Mice
Introduction: Recent studies have implicated oxidized lipids in the pathogenesis of pulmonary hypertension (PH) and suggest a role of lipotoxicity in the right ventricle (RV). Our lab demonstrated that HDL mimetic peptide 4F reduces levels of oxidized lipids and can rescue PH in rodents. Western diet (WD) fed low-density lipoprotein receptor knockout (LDL-R KO) mice have increased circulating oxidized lipids and develop atherosclerosis, but it is not known whether they develop PH and RV dysfunction or benefit from 4F therapy.
Hypothesis: We tested the hypothesis that WD fed LDL-R KO mice develop PH and RV dysfunction, which may be prevented by the HDL mimetic peptide 4F.
Methods: Male LDL-R KO mice (~2-3 month old, n=25) were fed either regular chow (n=8) or WD (n=17) for 12 weeks and monitored for development of PH and RV dysfunction. Mice on WD were further divided into two groups, WD (n=9) and those treated with HDL mimetic peptide 4F in drinking water for 12 weeks (n=8). Transthoracic echocardiography was performed to monitor cardiopulmonary hemodynamics. Direct RV and LV catheterization was performed terminally and RV hypertrophy index was calculated as weight ratio of RV/(LV+IVS). RV, LV and lung tissue were collected. Immunohistochemistry, Masson trichrome, Oil Red O stains and RT PCR were performed. Data are mean±SEM.
Results: WD fed LDL-R KO mice developed PH that was prevented by 4F (RV systolic pressure 44.76±3.95 mm Hg in WD vs. 29.87±0.55 mm Hg in WD+4F, p<0.05). WD fed LDL-R KO mice developed mild LV dysfunction (LVEF=48.87±0.83%) that was prevented by 4F (LVEF=57.22±1.64%, p<0.05). Interestingly, WD was not associated with either LV hypertrophy or LV pressure overload, and LV β-MHC and ANF expression was unchanged. PH was associated with pulmonary vascular remodeling, fibrosis and lipid deposition that were prevented by 4F. WD resulted in RV hypertrophy and dysfunction that were prevented by 4F [RV/(LV+IVS) 0.46±0.06 in WD vs. 0.28±0.01 in WD+4F, RVEF 44.55±0.85% in WD vs. 58.38±1.11% in WD+4F, p<0.05].
Conclusions: WD fed LDL-R KO mice develop PH and RV dysfunction not secondary to LV failure- further implicating oxidized lipids in PH pathogenesis. Both PH and RV dysfunction were prevented by 4F treatment highlighting its potential as a novel therapeutic agent.
Author Disclosures: C.M. Cunningham: None. S. Umar: None. S. Moazeni: None. G. Ruffenach: None. A. Centala: None. K. Nevab: None. M. Navab: None. M. Eghbali: None.
- © 2016 by American Heart Association, Inc.