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KCNMB1 −/− Mice as a Model of Pulmonary Arterial Hypertension
Author(s) -
Barnes Elizabeth,
Chen Chihhsin,
Barnes Shayna,
Kim Francis,
Lee Lori,
Alvira Cristina,
Cornfield David
Publication year - 2016
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.30.1_supplement.1138.3
Subject(s) - ventricle , pulmonary artery , pulmonary hypertension , hypoxic pulmonary vasoconstriction , medicine , cardiology , bk channel , hypoxia (environmental) , ventricular pressure , endocrinology , chemistry , potassium channel , blood pressure , organic chemistry , oxygen
Rationale The BK channel is a calcium‐sensitive ootassium (K + ) channel fundamental to the control of smooth muscle cell (SMC) tone. The pore‐forming α subunit is encoded by the KCNMA1 gene and its activity can be modified by the β1 subunit, encoded by the KCNMB1 gene. With an increase in cytosolic calcium concentration, the BK channel is activated, K + passively flows out of the channel and membrane hyperpolarization and vasorelaxation results. Loss of BK channel function can lead to membrane depolarization and vasoconstriction. Objective Pulmonary arterial hypertension (PAH) is a syndrome wherein there is an increase in pulmonary vascular resistance resulting in right ventricular heart failure. To assess the contribution of the BK channel β1 subunit in the development of PAH, the following hypothesis was tested: the expression of the BK channel β1 subunit modulates the pulmonary vascular response to chronic hypoxia. Methods Adult wild‐type (WT) and KCNMB1 −/− mice were exposed to normoxia at 21% O 2 , chronic hypoxia for 3 weeks at 10% O 2 or acute hypoxia for 5 minutes at 10% O 2 . Right ventricular systolic pressure (RVSP) and the weight ratio of right ventricle over left ventricle plus septum (RV/(LV+S)) were evaluated. Blood was collected by direct heart venipuncture and assayed for hematocrit levels. Peripheral pulmonary artery (PA) wall thickness was measured in vessels less than 100μm in diameter. Formalin‐fixed lung sections from mice exposed to chronic hypoxia were examined for β1 subunit and α‐SMA expression in PA. Peripheral pulmonary artery smooth muscle cells (PASMC) were isolated from WT and KCNMB1 −/− mice and assayed for β1, HIF‐1α, and phosphorylated myosin light chain (pMLC) expression. Results Under control conditions, there was no difference in RVSP between WT and KCNMB1 −/− mice. However, KCNMB1 −/− mice exhibited significantly higher RVSP compared to WT littermates with exposure to either acute or chronic hypoxia in the absence of histologic evidence of accentuated vascular remodeling. Both groups demonstrated similar increases in hematocrit, decreases in body weight, and maintained cardiac function after chronic hypoxic exposure. In lung tissue, β1 subunit expression was limited to PA less than 100μm in diameter. Moreover, pMLC, a determinant of SMC tone, was higher in SMC isolated from peripheral PA compared to those derived from larger PA. Conclusion The absence of the β1 subunit of the BK channel potentiates the pulmonary vascular response to both acute and chronic hypoxia. Functionally, in PASMC derived from the microvasculature, the β1 subunit plays a physiologically significant role in limiting the pulmonary vascular response to hypoxia. Compromised PASMC β1 expression may contribute to the pathogenesis of PAH.