Inducible Ift88-deficient mice show features consistent with mild pulmonary hypertension
Abstract
Intraflagellar transport protein 88 (IFT88) is essential for primary and motile cilia formation. In murine models and humans, Ift88 mutations contribute to renal cysts, epithelial proliferation and impaired immune responses. In mice, Ift88 knockout (KO) reduces airway cilia, increases airway epithelial proliferation and hyperreactivity, elevates IL-22 and decreases lung T regulatory cells. Pulmonary hypertension (PH) is a deadly disease marked by aberrant metabolism and immunoinflammatory mediators causing vasoconstriction and vascular remodeling. Endothelial-to-mesenchymal transition (EndMT) contributes to PH, and endothelial-specific Ift88 KO promotes endothelial proliferation and EndMT. We hypothesized that global loss of Ift88 causes PH. We assessed PH indices at 2 and 14 weeks postdeletion in tamoxifen-inducible Ift88 KO mice. These mice showed signs of PH, including increased right ventricular systolic pressure, cell proliferation in the walls of resistance arteries, and arterial wall thickening. At the early time point examined, we did not detect evidence of lung inflammation or EndMT. Because this is a tamoxifen-induced global Ift88 KO model, we cannot attribute the PH features to gene deletion in specific vascular cells, nor can we rule out the possibility that tamoxifen administration, global Ift88 deletion, the associated weight gain and food restriction may have influenced cardiovascular physiology in these mice.
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