Abstract 640: Indigo Naturalis, a Promising Herbal Medicine for Ulcerative Colitis, Can Induce Experimental Pulmonary Arterial Hypertension via Aryl Hydrocarbon Pathway

Abstract

Background: Indigo naturalis is a Chinese herbal medicine, whose dramatical effects for treatment of ulcerative colitis have been reported. However, some patients who took indigo naturalis developed pulmonary arterial hypertension (PAH), which is a poor prognostic disease with right ventricular (RV) failure and progressive remodeling of pulmonary vessels. Aims: We examined the reproducibility in experimental animals and elucidate the mechanisms for indigo naturalis to induce PAH. Methods and Results: Rats with 12-week intake of low-dose indigo naturalis (60 mg/kg body weight; corresponding to therapeutic dose for patients) did not induce PAH. However, RV and pulmonary vessel remodeling were identified in rats fed with high-dose indigo naturalis (600 mg/kg body weight) for 12 weeks. Significantly elevated RV systolic pressure was identified in rats administered with vascular endothelial growth factor-2 receptor blocker (Sugen 5416) and fed with indigo naturalis for 8 weeks compared to that of rats fed with normal diet (38.6 [38.2, 40.0] mmHg) vs. 31.9 [31.4, 34.6] mmHg, p < 0.001). Indigo, a major compound of indigo naturalis, also induced mild PAH. Indigo works as a ligand of aryl hydrocarbon receptor (AhR), and the mRNA levels of CYP1A1, downstream of AhR signal, were elevated in lungs. Rats with indigo naturalis and AhR antagonist gavage developed less pulmonary vessel remodeling than rats without AhR antagonist. Conclusions: The combination of Sugen 5416 and indigo naturalis can be a novel unique approach to generate rat PAH model without a hypoxic chamber. The effects of indigo naturalis to PAH might be mediated at least in part through activation of AhR-CYP1A1 pathway.