Stim‐activated TRPC‐ORAI channels in pulmonary hypertension induced by chronic intermittent hypoxia

Abstract

Obstructive sleep apnea (OSA), a breathing disorder featured by chronic intermittent hypoxia (CIH) is associated with pulmonary hypertension (PH). Rodents exposed to CIH develop pulmonary vascular remodeling and PH, but the pathogenic mechanisms are not well known. Overexpression of Stim-activated Transient Receptor Potential Channels (TRPC) and Calcium Release-Activated Calcium Channel Protein (ORAI) TRPC-ORAI Ca2+ channels (STOC) has been involved in pulmonary vascular remodeling and PH in sustained hypoxia. However, it is not known if CIH may change STOC levels. Accordingly, we studied the effects of CIH on the expression of STOC subunits in the lung and if these changes paralleled the progression of the vascular pulmonary remodeling and PH in a preclinical model of OSA. Male Sprague-Dawley rats (∼200 g) were exposed to CIH (5%O2, 12 times/h for 8 h) for 14, 21, and 28 days. We measured right ventricular systolic pressure (RVSP), cardiac morphometry with MRI, pulmonary vascular remodeling, and wire-myographic arterial responses to KCl and endothelin-1 (ET-1). Pulmonary RNA and protein STOC levels of TRPC1, TRPC4, TRPC6, ORAI 1, ORAI 2, and STIM1 subunits were measured by qPCR and western blot, and results were compared with age-matched controls. CIH elicited a progressive increase of RVSP and vascular contractile responses to KCl and ET-1, leading to vascular remodeling and augmented right ventricular ejection fraction, which was significant at 28 days of CIH. The levels of TRPC1, TRPC4, TRPC 6, ORAI 1, and STIM 1 channels increased following CIH, and some of them paralleled morphologic and functional changes. Our findings show that CIH increased pulmonary STOC expression, paralleling vascular remodeling and PH.

Role of Store-Operated Ca2+ Entry in the Pulmonary Vascular Remodeling Occurring in Pulmonary Arterial Hypertension

“…STIM1 and Orai1 expression and function were increased in aortas from spontaneously hypertensive rats [ 179 ]. In an experimental obstructive sleep apnea model induced in rats by chronic intermittent hypoxia (CIH) (5% inspired O 2 for 20 s, followed by 280 s of room air, 12 times per hour for 8 h a day for 14 to 28 days), Castillo-Galán et al showed the increased protein expression of Orai1, STIM1, and TRPC1, -C4, -C6 in the lungs of CIH rats [ 180 ]. Treatment of these rats with 2-APB decreased right ventricular systolic pressure (RVSP) and pulmonary vessel remodeling, which increased following CIH exposure [ 181 ].…”

The Action of 2-Aminoethyldiphenyl Borinate on the Pulmonary Arterial Hypertension and Remodeling of High-Altitude Hypoxemic Lambs

“…Notably, 20–25 representative resistance pulmonary arteries (150–250 μm of internal diameter) from each animal were selected for these analyses. Vascular density (number of arteries/area), percentage luminal area (luminal area/total area), and the wall, media, and adventitia thicknesses were calculated as described previously ( Herrera et al, 2008b ; Torres et al, 2015 ; Castillo-Galán et al, 2016 ; Castillo-Galan et al, 2020 ). The analysis of the microphotographs was performed with the Image Pro-Plus 6.2 software (Media Cybernetics, Inc., Rockville, MD, United States).…”

Cross-Talk between Mechanosensitive Ion Channels and Calcium Regulatory Proteins in Cardiovascular Health and Disease

“…arrhythmia [138] Orai Participation in SOCE [139,140] Pulmonary hypertension [140]; thrombosis [141] STIM SOCE activation [142] Hypertension and atherosclerosis [143][144][145];…”

“…When the EF-hand of STIM1 is mutated, it spontaneously aggregates with TRPC1 and then activates TRPC1 [159]. The interaction between TRP and STIM is implicated in the progression of many diseases, particularly some cardiovascular diseases such as arterial hypertension, atherosclerosis, or thrombosis [141,[143][144][145][146].…”