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

被引:14
作者
Castillo-Galan, Sebastian [1 ]
Arenas, German A. [1 ]
Reyes, Roberto V. [2 ]
Krause, Bernardo J. [3 ]
Iturriaga, Rodrigo [1 ]
机构
[1] Pontificia Univ Catolica Chile, Fac Ciencias Biol, Lab Neurobiol, Santiago, Chile
[2] Univ Chile, Lab Bioquim & Biol Mol Hipoxia, Santiago, Chile
[3] Univ OHiggins, Inst Ciencias Salud, Rancagua, Chile
关键词
chronic intermittent hypoxia; STOC; pulmonary hypertension; vascular remodeling; ARTERIAL SMOOTH-MUSCLE; OBSTRUCTIVE SLEEP-APNEA; CAROTID-BODY; CARDIOVASCULAR-DISEASE; NITRIC-OXIDE; CA2+ ENTRY; DYSFUNCTION; PRESSURE; PROLIFERATION; CIRCULATION;
D O I
10.1177/2045894020941484
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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(2+)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 (similar to 200 g) were exposed to CIH (5%O-2, 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.
引用
收藏
页码:13 / 22
页数:10
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