Castillo-Galán Sebastian, Arenas German A, Reyes Roberto V, Krause Bernardo J, Iturriaga Rodrigo
Laboratorio de Neurobiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Laboratorio de Bioquímica y Biología Molecular de la Hipoxia, Universidad de Chile, Santiago, Chile.
Pulm Circ. 2020 Oct 13;10(1 Suppl):13-22. doi: 10.1177/2045894020941484. eCollection 2020 Jul-Sep.
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 Ca 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%O, 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.
阻塞性睡眠呼吸暂停（OSA）是一种以慢性间歇性缺氧（CIH）为特征的呼吸障碍，与肺动脉高压（PH）相关。暴露于CIH的啮齿动物会发生肺血管重塑和PH，但致病机制尚不清楚。刺激激活的瞬时受体电位通道（TRPC）和钙释放激活钙通道蛋白（ORAI）的过表达，即TRPC-ORAI钙通道（STOC），已参与持续缺氧时的肺血管重塑和PH。然而，尚不清楚CIH是否会改变STOC水平。因此，我们研究了CIH对肺中STOC亚基表达的影响，以及这些变化是否与OSA临床前模型中肺血管重塑和PH的进展平行。将雄性Sprague-Dawley大鼠（约200 g）暴露于CIH（5%氧气，每小时12次，持续8小时）14、21和28天。我们测量了右心室收缩压（RVSP）、通过MRI进行心脏形态测量、肺血管重塑以及血管对氯化钾和内皮素-1（ET-1）的线肌电图反应。通过qPCR和蛋白质印迹法测量肺RNA和蛋白质中TRPC1、TRPC4、TRPC6、ORAI 1、ORAI 2和STIM1亚基的STOC水平，并将结果与年龄匹配的对照组进行比较。CIH引起RVSP以及血管对氯化钾和ET-1的收缩反应逐渐增加，导致血管重塑和右心室射血分数增加，在CIH 28天时显著。CIH后TRPC1、TRPC4、TRPC 6、ORAI 1和STIM 1通道水平升高，其中一些与形态学和功能变化平行。我们的研究结果表明，CIH增加了肺STOC表达，与血管重塑和PH平行。
