Crucial Role of Stromal Interaction Molecule-Activated TRPC-ORAI Channels in Vascular Remodeling and Pulmonary Hypertension Induced by Intermittent Hypoxia

Abstract

Obstructive sleep apnea (OSA), a sleep breathing disorder featured by chronic intermittent hypoxia (CIH), is associate with pulmonary hypertension. Rats exposed to CIH develop lung vascular remodeling and pulmonary hypertension, which paralleled the upregulation of stromal interaction molecule (STIM)-activated TRPC-ORAI Ca2+ channels (STOC) in the lung, suggesting that STOC participate in the pulmonary vascular alterations. Accordingly, to evaluate the role played by STOC in pulmonary hypertension we studied whether the STOC blocker 2-aminoethoxydiphenyl borate (2-APB) may prevent the vascular remodeling and the pulmonary hypertension induced by CIH in a rat model of OSA. We assessed the effects of 2-APB on right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, α-actin and proliferation marker Ki-67 levels in pulmonary arterial smooth muscle cells (PASMC), mRNA levels of STOC subunits, and systemic and pulmonary oxidative stress (TBARS) in male Sprague-Dawley (200 g) rats exposed to CIH (5% O2, 12 times/h for 8h) for 28 days. At 14 days of CIH, osmotic pumps containing 2-APB (10 mg/kg/day) or its vehicle were implanted and rats were kept for 2 more weeks in CIH. Exposure to CIH for 28 days raised RVSP > 35 mm Hg, increased the medial layer thickness and the levels of α-actin and Ki-67 in PASMC, and increased the gene expression of TRPC1, TRPC4, TRPC6 and ORAI1 subunits. Treatment with 2-APB prevented the raise in RVSP and the increment of the medial layer thickness, as well as the increased levels of α-actin and Ki-67 in PASMC, and the increased gene expression of STOC subunits. In addition, 2-APB did not reduced the lung and systemic oxidative stress, suggesting that the effects of 2-APB on vascular remodeling and pulmonary hypertension are independent on the reduction of the oxidative stress. Thus, our results supported that STIM-activated TRPC-ORAI Ca2+ channels contributes to the lung vascular remodeling and pulmonary hypertension induced by CIH.

Chronic intermittent hypoxia‐induced cardiovascular and renal dysfunction: from adaptation to maladaptation

“…aorta, mesenteric, pulmonary and ophthalmic arteries) (Arnaud et al., 2018; Friedman et al., 2014; Mentek et al., 2018; Norton et al., 2011; Troncoso Brindeiro et al., 2007). In turn, CIH promotes irreversible oxidative protein modifications (Arnaud et al., 2018; Moya et al., 2016; Ozcan et al., 2022; Siques et al., 2014; Zhou, Wang, et al., 2014) and lipid peroxidation (Castillo‐Galán et al., 2022; Zhou, Wang, et al., 2014). This excessive ROS production can result from a CIH‐induced imbalance between pro‐ and antioxidant systems (Lavie, 2015).…”

Metabolic Deregulation in Pulmonary Hypertension

“…Numerous publications have reported gene expression regulations caused by PAH in lungs from humans (e.g. : [26,1]) and animal models of PAH [27,28]), but they are limited to comparing the expression levels of genes in lungs of PAH and healthy subjects. Our study goes further by adopting the Genomic Fabric Paradigm (GFP) [29] that takes full advantage of the simultaneous profiling of tens of thousands of genes on several biological replicas.…”