Abstract 20334: Dysregulation in Metabolic and Angiogenic Pathways Are Associated Defective Right Ventricular Adaptation in Fischer Rats With Severe Pulmonary Arterial Hypertension
Introduction: Fischer rats exhibit a very high mortality in the SU5416 (SU)/ chronic hypoxia (CH) model of severe pulmonary arterial hypertension (PAH) compared to Sprague Dawley (SD) rats, despite nearly identical hemodynamic changes. Poor survival was associated with greater dilatation and reduced contractility of the right ventricle (RV) suggesting a strain-specific defect in RV adaptation to increased afterload. The aim of this study was to explore the molecular mechanisms responsible for this marked difference in adaptive RV remodeling in Fischer compared to SD rats.
Methods/Results: PAH was induced by a single injection of SU (20mg/kg, sc), or vehicle (Control), followed by a 3-week exposure to CH (10% O2). Elevation in RVSP and RV hypertrophy (RV/LV+S mass ratio) in SD (Harlan, USA) and Fischer (CDF, Charles River) rats in response to SU/CH. Echocardiography (Vevo 2100, Visual Sonics) was performed weekly to assess RV structure and function. Fischer rats exhibited far greater RV dilatation (diastolic RV internal diameter/LV internal diameter; RVID/LVID) and reduction in cardiac output compared to SD. As well, capillary density was significantly reduced in Fischer rats as assessed by CD31 immunostaining and fluorescent microangiography. RNA expression was assayed in the RV at 4 weeks post SU using Affymetrix Rat Gene 2.0ST and Affymetrix miRNA 4.0 gene chips, showing a down-regulation of genes related to fatty acid metabolism genes (SLC27A1, ACADSB, ACSL1, DECR1, LIPE, HADHA, CYP4B1), as well as peroxisome proliferator-activated Receptor gamma coactivator 1 α (PGC1α), which has previously been implicated in metabolic dysfunction of RV decompensation. A focused angiogenesis RT-PCR array showed significant alterations in the expression of a variety of genes related to angiogenesis and vascular homeostasis, including prostaglandin synthase 1, endoglin and integrin beta chain beta3, Akt1, tumor narcotic factor, epidermal growth factor and angiopoietin 1 in Fischer versus SD rats.
Conclusion: Inadequate RV adaptation in response to severe PAH in Fischer compared to SD rats is associated with blunted expression of genes controlling myocardial metabolism and neovascularization, likely underlying strain-dependent defects in RV compensation.
Author Disclosures: C.M. Suen: None. K.R. Chaudhary: Research Grant; Significant; Entelligence Young Investigator award- Actelion Pharmaceuticals US Inc.. Y. Deng: None. A. Yang: None. B. Jiang: None. D.J. Stewart: Research Grant; Significant; United Therapeutics Inc.. Ownership Interest; Significant; Northern Therapeutics Inc..
- © 2016 by American Heart Association, Inc.