Role of the aryl hydrocarbon receptor in sugen 5416-induced experimental pulmonary hypertension

Dean, Afshan and Gregorc, Teja and Docherty, Craig K. and Harvey, Katie Y. and Nilsen, Margaret and Morrell, Nicholas W. and MacLean, Margaret R. (2018) Role of the aryl hydrocarbon receptor in sugen 5416-induced experimental pulmonary hypertension. American Journal of Respiratory Cell and Molecular Biology, 58 (3). pp. 320-330. ISSN 1535-4989

Text (Dean-etal-AJRCMB-2018-Role-of-the-aryl-hydrocarbon-receptor-in-sugen-5416-induced-experimental-pulmonary-hypertension)
Accepted Author Manuscript

Download (1MB)| Preview


    Rats dosed with the vascular endothelial growth factor inhibitor Sugen 5416 (Su), subjected to hypoxia, and then restored to normoxia have become a widely used model of pulmonary arterial hypertension (PAH). However, the mechanism by which Su exacerbates pulmonary hypertension is unclear. We investigated Su activation of the aryl hydrocarbon receptor (AhR) in human pulmonary artery smooth muscle cells (hPASMCs) and blood outgrowth endothelial cells (BOECs) from female patients with PAH. We also examined the effect of AhR on aromatase and estrogen levels in the lung. Protein and mRNA analyses demonstrated that CYP1A1 was very highly induced in the lungs of Su/hypoxic (Su/Hx) rats. The AhR antagonist CH223191 (8 mg/kg/day) reversed the development of PAH in this model in vivo and normalized lung CYP1A1 expression. Increased lung aromatase and estrogen levels in Su/Hx rats were also normalized by CH223191, as was AhR nuclear translocator (ARNT [HIF-1b]), which is shared by HIF-1a and AhR. Su reduced HIF-1a expression in hPASMCs. Su induced proliferation in BOECs and increased apoptosis in human pulmonary microvascular ECs and also induced translocation of AhR to the nucleus in hPASMCs. Under normoxic conditions, hPASMCs did not proliferate to Su. However, when grown in hypoxia (1%), Su induced hPASMC proliferation. In combination with hypoxia, Su is proliferative in hPASMCs and BOECs from patients with PAH, and Su/Hx-induced PAH in rats may be facilitated by AhR-induced CYP1A1, ARNT, and aromatase. Inhibition of AhR may be a novel approach to the treatment of pulmonary hypertension.