Figure 7.

Lum Increases WT CFTR Protein Expression by a Proteostatic Mechanism and Restores Cerebral Perfusion in SAH

(A) Cerebral arteries isolated from naïve mice treated with Lum (3 mg/kg intraperitoneally daily for 2 days; n = 6) have higher CFTR protein expression than arteries collected from vehicle controls (n = 7). (B) Lum does not influence cerebral artery CFTR mRNA expression (n = 5 for both groups). (C) Lum (6 μmol/l; 24 h) increases CFTR protein expression in baby hamster kidney fibroblast cells stably expressing human CFTR (n = 13 for both groups). (D) Lum does not influence CFTR mRNA expression in this system (n = 6 for both groups). (E) Cerebral arteries isolated from mice with SAH (2 days post-SAH induction) have reduced CFTR protein expression (n = 5) relative to arteries isolated from sham-operated controls (n = 6). Lum treatment in vivo (3 mg/kg intraperitoneally daily for 2 days) eliminates this reduction in cerebral artery CFTR protein expression (n = 6). (F) Lum treatment in vivo reduces myogenic tone in olfactory arteries isolated from mice with SAH. Mean maximal vessel diameters at 45 mm Hg (dia_max) are sham: 91 ± 3 μm; n = 7 from 4 mice; SAH: 86 ± 2 μm; n = 6 from 3 mice; SAH+Lum: 87 ± 4 μm; n = 7 from 4 mice (1-way analysis of variance: p = NS). (G) Representative magnetic resonance perfusion maps that were used to determine CBF. SAH stimulated a reduction in cerebral perfusion; Lum treatment significantly improved cerebral perfusion in mice with SAH (sham: n = 6; SAH: n = 5; SAH+Lum: n = 6). All data are mean ± SEM. In (A to D), * p < 0.05 for an unpaired comparison with a t-test; in (E and G), *p < 0.05 for unpaired comparisons to sham with a 1-way analysis of variance test and Dunnett’s post hoc test. In (F), *p < 0.05 for unpaired comparisons to sham with a 2-way analysis of variance and Tukey’s post hoc test. Abbreviations as Figures 1, 2, and 3.