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RyR2/Ca2+ release channel is crucial for pulmonary arterial hypertension
Author(s) -
Zheng YunMin,
Wang YongXiao
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.906.11
Subject(s) - ryanodine receptor , ryanodine receptor 2 , hypoxia (environmental) , medicine , pulmonary hypertension , pulmonary artery , constriction , cardiology , endocrinology , chemistry , pharmacology , receptor , organic chemistry , oxygen
Pulmonary arterial hypertension (PAH) is a devastating lung disease. However, the underlying molecular mechanisms remain to be fully elucidated. Ryanodine receptor‐2 (RyR2) is important for cardiovascular functions. In this study, thus, we sought to investigate the potentially crucial role of this Ca2+ release channel in PAH. Our investigations demonstrate that RyR2 gene knockout (KO) abolishes the increased right ventricular pressure and weight (i.e., PAH) in mice after chronic hypoxia (hypoxic exposure for 3 weeks). The chronic hypoxic increase in pulmonary arterial constriction and muscle layer are both eliminated in RyR2 KO mice. RyR activity, Ca2+ release and basal [Ca2+]i in pulmonary artery smooth muscle cells (PASMCs) are all augmented in control, but not in RyR2 KO mice. These exciting animal studies may have a general significance in humans, as RyR activity is significantly enhanced in PASMCs of chronic obstructive lung disease (COPD) patients with PAH. Fascinatingly, treatment with tetracaine (a classic RyR antagonist that is clinically used in anesthesia) blocks chronic hypoxia‐induced PAH and cellular responses. In conclusion, our findings for the first time provide breakthrough evidence that chronic hypoxia causes RyR2 activation, Ca2+ release, pulmonary arterial constriction/remodeling, and ultimately PAH; and RyR antagonists may become new and effective drugs in the treatment of PAH.