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bioRxiv · 10.1101/2023.10.05.561143

Aquaporin 1 confers apoptosis resistance in pulmonary arterial smooth muscle cells from the SU5416 hypoxia rat model

Yun, X.·Niedermeyer, S.·Andrade, M.·Jiang, H.·Suresh, K.·Kolb, T.·Damarla, M.·Shimoda, L.
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Abstract

Pulmonary arterial hypertension (PAH) is a deadly condition that arises from increased pulmonary vascular resistance due to contraction and remodeling of the pulmonary arteries. The structural changes that occur in the pulmonary arteries include thickening of the medial (smooth muscle) layer resulting from increased proliferation and resistance to apoptosis. The mechanisms underlying apoptosis resistance in PAH are not fully understood. In cancer cells, high expression of aquaporin 1 (AQP1), a water channel, is associated with apoptosis resistance. We previously showed functional AQP1 protein was expressed in pulmonary arterial smooth muscle cells (PASMCs) and was upregulated in pre-clinical models of pulmonary hypertension. Whether AQP1 controls susceptibility of PASMCs to apoptosis in pre-clinical models of PAH is unknown. In this study, we used PASMCs isolated from control rats and rats exposed to SU5416 plus hypoxia (SuHx) to test the role of AQP1 in modulating apoptosis in PASMCs. We found that elevated levels of AQP1 in PASMCs from pulmonary hypertensive rats were necessary for resistance to apoptosis, and that apoptosis resistance could be conferred by increasing expression of AQP1 in PASMCs from control rats. Moreover, in exploring the downstream pathways involved, we found AQP1 levels influence the expression of Bcl-2, with enhanced AQP1 levels corresponding to increased Bcl-2 expression, resulting in reductions in the ratio of BAX to Bcl-2 as are typically associated with apoptosis resistance. These early results provide a mechanism by which AQP1 can regulate PASMC fate and suggest further investigation could provide additional clues regarding whether AQP1-mediated apoptosis resistance contributes to PAH development or progression and whether AQP1 might be a suitable target for therapy.

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Yun, X., Niedermeyer, S., Andrade, M., Jiang, H., Suresh, K., Kolb, T., Damarla, M., Shimoda, L.. 2023-10-06. Aquaporin 1 confers apoptosis resistance in pulmonary arterial smooth muscle cells from the SU5416 hypoxia rat model. https://doi.org/10.1101/2023.10.05.561143

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