Alterations in Genes Associated with Bioactive Lipid Pathways during Development of Pulmonary Hypertension in Rat SU5416‐Hypoxia Model of Severe Pulmonary Arterial Hypertension

Abstract

Background Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vascular system characterized by sustained elevation in resting mean pulmonary arterial pressure (>25 mmHg) with presence of occlusive vascular remodeling and progressive loss of microvasculature. PAH patients have a poor five‐year survival rate of only ~50% and the primary cause of death for PAH patients is the right (‐sided) heart failure. Better understanding of pathophysiology of PAH and RHF is required to find novel therapies. In this project, using a rat model of severe PAH, we explored the alterations in expression of genes involved in bioactive lipid pathways in the lungs and the right ventricle (RV) during development of PAH. Methods Adult male Sprague Dawley rats were administered a single injection of SU5416 (SU; 20 mg/kg, subcutaneous) and subjected to 3 weeks of hypoxia (10% O2) followed by 4 weeks of normoxia (room air), SUHx model of sever PAH. Right ventricular systolic pressure (RVSP) was measured, and heart and lung samples were collected at 1, 3, 7, 21 and 49‐days post SU injection. Histological analysis was conducted to confirm vascular remodeling in the lungs and development of RV hypertrophy (RVH; RV/LV+S). RTqPCR was performed to evaluate gene expression changes in the genes related to bioactive lipids pathways. Results In response to SUHx, progressive increase in RVSP and RVH was observed. Histology of lungs and heart samples confirmed pulmonary vascular and RV remodeling at 7 weeks post SU in the SUHx model. We observed increase in expression of ALOX‐5 in the RV and lungs of SUHx rats, compared to controls. Furthermore, alterations in various cytochrome P450 (CYP) isozymes were observed in the RV and lungs of SUHx rats compared to controls. Conclusions Together, we have identified unique changes in bioactive lipid pathway genes in the lungs and the RV that were associated with development of PAH and RV remodeling in SUHx model. Further studies are ongoing to confirm the role of the candidate genes in pathophysiology of PAH and development of RHF.