P7 Investigating the role of obesity and cytochrome P450 1A1 in pulmonary arterial hypertension using a novel rat model

Rationale Pulmonary hypertension (PH) is a debilitating disease characterised by elevated pulmonary arterial pressure, vascular remodelling, and right ventricular (RV) dysfunction. Notably, 30% – 50% of pulmonary arterial hypertension (PAH) patients are obese and the severity of their disease is associated with body mass index. A growing body of evidence suggests that dysregulated estrogen metabolism by cytochrome P450 (CYP) 1 enzymes may precipitate PAH in obese individuals by forming mitogenic 16-hydroxyestrogens (Dean et al., 2018; Mair et al., 2019). Herein, we characterise a novel rat model of obesity-PH and investigate the therapeutic potential of inhibiting CYP1A1 in these animals. Methods Male and female Wistar Han rats were fed on a high fat diet (60% energy from fat) for 12 weeks. On week 6, animals were administered the vascular endothelial growth factor receptor antagonist Sugen (30 mg/kg; subcutaneous). In some experiments, male rats were treated with the CYP1A1 inhibitor hesperetin (100 mg/kg/day; oral gavage; 14 days). Control animals were maintained on standard rodent diet. PH was quantified by RV pressure-volume loop and heart chambers were weighed to determine right ventricle hypertrophy. Gene expression was assessed by qRT-PCR. Results Exposure to a high fat diet significantly elevated RV systolic pressure (RVSP; ~4 mmHg, p<0.05) and RV weight in rats of both sexes. Sugen administration upregulated the CYP1A1 and CYP1B1 genes in the lungs of male (~400-fold and ~20-fold, respectively p<0.0001) and female animals (~200-fold and ~20-fold, respectively p<0.0001). Sugen further elevated RVSP in obese male rats (~4 mmHg p<0.05) but had no effect in obese females or lean controls. Therapeutic intervention with hesperetin attenuated the development of PH in Sugen-treated obese males, indicated by a significant decrease in RVSP (~7 mmHg, p<0.001). Conclusions In sum, these data suggest that obesity is a risk factor for the development of PAH and provide a rationale for pharmacological inhibition of CYP1A1 in obese PAH patients.