Effects of 2‐APB, a Stim‐Activated TRPC‐ORAI Channels Blocker, on the Vascular Remodeling and Pulmonary Hypertension Induced by Chronic Intermittent Hypoxia

Abstract

Obstructive sleep apnea (OSA), a breathing disorder characterized by episodes of chronic intermittent hypoxia (CIH), is an independent risk for systemic hypertension. Furthermore, 20–60% of OSA patients develop moderate pulmonary hypertension (PH). Rats exposed to CIH developed pulmonary vascular remodeling and PH, but the mechanisms underlaying these responses are not well known. Stim‐activated TRPC‐ORAI channel (STOC), cationic calciumpermeable channels, are overexpressed in the lung and plays a key role in the development of pulmonary vascular remodeling and PH in animals exposed to sustained hypoxia. We previously demonstrated that STOC are overexpressed in lung of rats exposed to CIH. However, whether these channels are involved in the pulmonary vascular remodeling and PH induced by CIH have not been addressed. Thus, we studied the effects of treatment of 2‐aminoethyldiphenylborinate (2‐APB), a STOC blocker, in rats exposed to CIH. Male Sprague‐Dawley rats (~200g) were exposed for 28 days to CIH (5% O2, 12 times/h, for 8h). At 14 days of CIH, rats under anesthesia were implanted with osmotic pumps containing 2‐APB (10 mg/kg/day) or its vehicle, and then rats were exposed to CIH for 14 more days. At the end of CIH exposure, the right ventricular systolic pressure (RVSP) was measure under anesthesia with urethane/α‐cloralose (800 mg/kg, i.p). Animals were then euthanized and lungs dissected to determine vascular remodeling in arteries of 200–300 μm, and the mRNA levels of the STOC forming subunits TRPC1, TRPC4, TRPC6, ORAI 1 and ORAI 2 by qPCR. 2‐APB infusion prevented the increase of the RVSP (36.5 ± 1.1 mmHg vs. 24.7 ± 1.6 mmHg, 28d‐CIH vs. 2‐APB respectively), and the pulmonary vascular remodeling (66.3 ± 9.4 % vs 48.2 ± 3.5 %, CIH, 28d‐CIH vs. 2‐APB, respectively). In addition, 2‐APB treatment reverted the increase in the mRNA levels of TRPC1, TRPC4 and TRPC6, but induced an overexpression of ORAI 1, while ORAI 2 remained unchanged. Present results suggest that STOC plays a key role in the developing of the vascular remodeling and pulmonary hypertension induced by CIH.Support or Funding InformationSUPPORTED BY FONDECYT 1150040 and 1180341