Aqp-1 Gene Knockout Attenuates Hypoxic Pulmonary Hypertension of Mice

Abstract

Objective— Hypoxic pulmonary hypertension (HPH) is characterized by proliferative vascular remodeling. Abnormal pulmonary artery smooth muscle cells proliferation and endothelial dysfunction are the primary cellular bases of vascular remodeling. AQP1 (aquaporin-1) is regulated by oxygen level and has been observed to play a role in the proliferation and migration of pulmonary artery smooth muscle cells. The role of AQP1 in HPH pathogenesis has not been directly determined to date. To determine the possible roles of AQP1 in the pathogenesis of HPH and explore its possible mechanisms. Approach and Results— Aqp1 knockout mice were used, and HPH model was established in this study. Primary pulmonary artery smooth muscle cells, primary mouse lung endothelial cells, and lung tissue sections from HPH model were used. Immunohistochemistry, immunofluorescence and Western blot, cell cycle, apoptosis, and migration analysis were performed in this study. AQP1 expression was upregulated by chronic hypoxia exposure, both in pulmonary artery endothelia and medial smooth muscle layer of mice. Aqp1 deficiency attenuated the elevation of right ventricular systolic pressures and mitigated pulmonary vascular structure remodeling. AQP1 deletion reduced abnormal cell proliferation in pulmonary artery and accompanied with accumulation of HIF (hypoxia-inducible factor). In vitro, Aqp1 deletion reduced hypoxia-induced proliferation, apoptosis resistance, and migration ability of primary cultured pulmonary artery smooth muscle cells and repressed HIF-1α protein stability. Furthermore, Aqp1 deficiency protected lung endothelial cells from apoptosis in response to hypoxic injury. Conclusions— Our data showed that Aqp1 deficiency could attenuate hypoxia-induced vascular remodeling in the development of HPH. AQP1 may be a potential target for pulmonary hypertension treatment.

Ca2+ Mediates HIF-dependent Upregulation of Aquaporin 1 in Pulmonary Arterial Smooth Muscle Cells

“…Thus, it remains unknown whether AQP1 mRNA levels were increased by chronic hypoxia in these particular tissues, as has been reported previously for hypoxic rats and mice (1,9,16), or whether digoxin treatment transcriptionally inhibited AQP1. Nonetheless, these experiments confirm previous findings of increased AQP1 protein levels in the lungs of hypoxic mice (18,25) and rats (16) and provide proof-ofconcept that elevations in lung AQP1 levels during in vivo CH could involve HIF.…”

Aquaporins in lung health and disease: Emerging roles, regulation, and clinical implications

“…Chronic hypoxia exposure as in Hypoxia pulmonary hypertension (HPH) mouse model AQP1↑ AQP1 was upregulated in both endothelia and smooth muscle cells which showed dysfunction and proliferation, respectively. AQP1 deficiency protected from these effects in gene KO mice.. [73] Lung phlegm-blocking rat model (SO2 inhalation + cold wind exposure) AQP1↓AQP5↓ Reversal of the levels of these AQPs using natural products had expectorant effects [74] Deep hypothermia cardiac arrestinduced Ischemia/reperfusion lung injury in rat model AQP5↓ cAMP-PKA signaling pathway implicated in AQP5 regulation [75] Acute cold exposure rat model (−25 °C) AQP5↓ Body core temperature of the cold-exposed rats was…”

The role of NOX4 in pulmonary diseases

“…Liu et al, 2018). HPH is a progressive disease characterized by elevated pulmonary vascular resistance, which causes right ventricular failure and significantly increases morbidity and mortality (M. Liu et al, 2019;K. Wu, Zhang, et al, 2017).…”

“…Sustained hypoxia promotes the development of PAH and leads to hypoxic pulmonary hypertension (HPH; Lahm & Chakinala, 2013; J. Liu et al, 2018). HPH is a progressive disease characterized by elevated pulmonary vascular resistance, which causes right ventricular failure and significantly increases morbidity and mortality (M. Liu et al, 2019; K. Wu, Zhang, et al, 2017). Hypoxia activates the NOX4/NF‐κB signaling pathway, increases NOX4 expression, activates PASMCs, and ultimately promotes HPH (Lu et al, 2010).…”