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Targeting the Right Ventricle as a Treatment Strategy for Pulmonary Arterial Hypertension
Author(s) -
Gorr Matthew W.,
Liang Wenjing,
Muthusamy Abinaya,
Sriram Krishna,
Insel Paul A.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.568.15
Subject(s) - ventricle , hypoxia (environmental) , medicine , cardiology , vasodilation , pulmonary hypertension , lung , ventricular remodeling , pulmonary artery , receptor , heart failure , endocrinology , chemistry , organic chemistry , oxygen
Pulmonary arterial hypertension (PAH) is characterized by remodeling of the pulmonary artery within the lung that leads to increased pulmonary vascular resistance (PVR). This increase in PVR can result in progressive remodeling of the right ventricle (RV) and eventual right heart failure. Current therapy aims to decrease PVR via vasodilation of the PA, but this strategy does not work for some patients, and is not a cure for the disease. This study aims to uncover novel therapeutic targets by assessing the RV for expression of G protein‐coupled receptors (GPCRs) during PAH. GPCRs are the target of more than 30% of approved drugs and regulate multiple cellular processes by activation on the cell membrane. We utilized a rat model of PAH in which Sprague Dawley rats were placed in hypoxia (10% O2) for two weeks, or normoxia as a control (n=3–4/treatment). Placement in hypoxia resulted in RV remodeling evident by an increase in the RV weight/left ventricle (LV) + septum weight (hypoxia‐treatment: 0.458 ± 0.036 vs. control rats: 0.210 ± 0.020; mean ± standard deviation, Student's t‐test p<0.0001). We then utilized RNA sequencing (RNA‐seq) of the RV and the left ventricle (LV) tissue coupled with differential expression analysis to identify GPCRs expressed with significantly (false discovery rate <0.1) altered expression in the RV of hypoxia‐treated rats compared to controls. In the RV, 37 GPCRs were altered in expression in hypoxia‐treated rats vs. control rats compared to 7 GPCRs altered in the LV. To examine the cell‐specific expression of these targets, cardiac myocytes and fibroblasts were isolated from a mouse model of PAH (10% O2 for 3 weeks with weekly injection of SU5416). qPCR of the target GPCRs revealed that most of the differentially expressed GPCRs were altered in the cardiac myocytes but not in the fibroblasts. These results indicate that a subset of genes is differentially expressed in the RV compared to the LV both in normoxia and hypoxia, particularly in the cardiac myocytes. This raises the possibility that treatments for PAH could be directed at GPCRs selectively expressed in RV remodeling, thus providing a novel means of treating an unmet need for patients with RV hypertrophy and failure. Support or Funding Information Supported by NIH Grant: T32HL007444‐34 and DoD Grant: W81XWH‐14‐1‐0372 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .