(769.1) Blockade of Stim-activated TRPC-ORAI Channels Prevents Vascular Remodeling and  Pulmonary Hypertension Induced by Chronic Intermittent Hypoxia

Poster Board Number: E592

Sebastian Castillo-Galan (Pontificia Universidad Catolica de Chile), Barbara Riquelme (Pontificia Universidad Catolica de Chile), Rodrigo Iturriaga (Pontificia Universidad Catolica de Chile)

Obstructive sleep apnea (OSA), a sleep breathing disorder featured by chronic intermittent hypoxia (CIH), is associate with mild pulmonary hypertension (PH). Rats exposed to CIH developed pulmonary vascular remodeling and PH, but the pathogenic mechanisms are not well known. In addition, CIH overexpressed Stim-activated TRPC-ORAI channels (STOC) in the lung, which paralleled the increase of right systolic ventricle pressure (RVSP) and pulmonary vascular remodeling. Accordingly, we tested weater a treatment with the STOC bloker 2-Aminoethyl diphenylborinate (2-APB), started from day 14 days to exposure to CIH may reduce vascular remodelling and PH. Male Sprague-Dawley rats (~200g) were exposed  CIH (5% O2, 12 times/h for 8h). At 14 days, osmotic pumps containing 2-APB (10 mg/kg/day, n=7) or its vehicle (n=7) were implanted, and rats were keep in CIH for 2 more weeks. At the end of CIH exposure, RVSP was measured in urethane-chloralose anesthetized rats. Animals were euthanized and lungs were removed to determine vascular remodeling and mRNA levels of the STOC forming subunits TRPC1, TRPC4, TRPC6, ORAI 1 and ORAI 2 by qPCR. CIH-treated rats were compared with aged-matched normoxic controls. 2-APB reduced the increase of RVSP (24.7 ± 1.6 vs. 36.5 ± 1.1 mmHg, 2-APB vs vehicle, respectively, p lt; 0.05) and the medial layer thickness of arteries (50-300 µm) (43.4 ± 1.1 vs. 66.5 ± 2.9 %, 2-APB vs vehicle, respectively, p lt; 0.05). In addition, 2-APB prevented the increase of α-actin-ir (8.8 ± 0.4 vs. 14.3 ± 0.6 pixels/μm2, 2-APB and vehicle respectively, p lt; 0.05), and to KI67 positive cells (3.9 ± 0.8 vs. 6.3 ± 1.1 %, 2-APB and vehicle, respectively, p lt; 0.05). In addition, 2-APB treatment reverted the increased mRNA levels of TRPC1, TRPC4 and TRPC6, but induced an overexpression of ORAI 1, while ORAI 2 remained unchanged. The present results show that 2-APB treatment prevented the vascular pulmonary alterations induced by CIH, suggesting that the blockade of STOC may potentially be used to treat the pulmonary hypertension induced by OSA.

SUPPORTED BY FONDECYT 1211443