Abstract 20172: A Novel Mutation in Hif1α in Sprague Dawley Rats is Associated With Hyper-Responsiveness to Su5416 and Severe Pulmonary Arterial Hypertension
Introduction: Our lab has identified a unique sub-strain of SD rats that is hyper-responsive (HR) to SU5416 (SU) alone and develops severe progressive PAH in response to single injection of SU, even in absence of chronic hypoxia (CH).
Hypothesis: We hypothesized that the HR phenotype in response to SU is conferred by genetic determinants that potentiate the response to VEFR2 blockade.
Methods and Results: Male and female rats were injected with SU (20mg/kg, sc) or vehicle (control). Right ventricular systolic pressure (RVSP) was measured at 7 weeks after SU injection. In absence of CH, 72% (13 of 18) male SD rats demonstrated HR-phenotype and developed severe PAH in response to SU with mean RVSP of 97±18 mmHg; whereas only 27% (7 of 26) of the female rats showed HR-phenotype. Furthermore, crossing non-responsive male and female rats from the HR colony markedly decreased the proportion of rats exhibiting HR phenotype in the F1-generation (HR 15% and 0%, male vs. female, respectively), consistent with the presence of modifier genes. Using whole genome-wide exome sequencing approach, we identified a number of mutations unique to the HR SD colony. Bioinformatics analysis of the data identified several candidate genes exhibiting mutations tightly associated with the HR phenotype, including the hypoxia inducible factor 1α (HIF1α), SP110, cingulin-1 (CGNL1) and pituitary tumor-transforming gene 1 (PTTG1). Interestingly, an INDEL mutation in HIF1α was found in all SD rats, both in HR and non-HR. However, mutations in PTTG1 and CGNL1 genes were present only in the HR SD rats. In addition, HR rats showed exacerbated hemodynamic response to CH as compared to the non-HR SD rats (RVSP: 72±5 mmHg vs. 49±4 mmHg) consistent with increased hypoxia signaling and a gain-of-function HIF1α mutation. We also observed significantly higher HIF1α and BNIP3 (a downstream target of HIF1α) expression in the lungs of HR SD rats.
Conclusion: A previously unrecognized mutation in HIF1α in SD rats is associated with increased susceptibility to severe PAH, which requires the presence of mutations in additional unique modifier genes. These findings may provide insight into possible genetic determinants influencing the penetrance of the PAH phenotype in humans harboring disease-causing mutations.
Author Disclosures: K.R. Chaudhary: Research Grant; Significant; Entelligence Young Investigator award- Actelion Pharmaceuticals US Inc.. Y. Deng: None. A. Yang: None. E. Cuppen: None. D.J. Stewart: Research Grant; Significant; United Therapeutics Inc.. Ownership Interest; Significant; Northern Therapeutics Inc..
- © 2016 by American Heart Association, Inc.