【摘 要】
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Background: Chronic hypoxia is a key trigger of pulmonary vascular remodeling in puhnonary hypertension (PH).The mammalian target of rapamycin (mTOR) is involved in cell proliferation, which is negati
【机 构】
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Department of Physiology,Capital Medical University,Beijing,China
【出 处】
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International Conference for Physiological Sciences 2012(201
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Background: Chronic hypoxia is a key trigger of pulmonary vascular remodeling in puhnonary hypertension (PH).The mammalian target of rapamycin (mTOR) is involved in cell proliferation, which is negatively regulated by tuberous sclerosis complex 1(TSC1).However, whether TSC1/mTOR pathway is involved in hypoxia-induced PH is still unknown.Objective: To find out whether TSC1/mTOR pathway is involved in PH and provide a target for its therapy.Methods: Conditional endothelial cell-specific haploinsufficiency of TSC1 mice [Tek-cre(+)/TSC1 fx/+] and wild type mice [Tek-cre(-)/TSC1 fx/+] (provided by prof.Kai-feng Xu)were used.The mice were exposed to either hypoxia (10% O2) or normoxia (21% O2), then the right ventricular systolic pressure (RVSP), and index of right ventricular hypertrophy (RVHI) were measured.Histological measurement was used to estimate the distal vascular remodeling.Western blot was used to detect the change of protein expression in mice lungs.Results: No obvious differences were found in those two genotypic mice under normoxia.After hypoxia, although RVSP and RVHI of those two genotypic mice was gradually increased, Tekcre(+)/TSC1 fx/+ mice were higher after 3 weeks (RVSP: 22.79±0.31 vs.19.95±0.97 mmHg, P<0.05;0.32±0.01 vs.0.25t0.02, P<0.05).The small puhnonary arteries of both Tek-cre(+)/TSClfx/+ and Tek-cre(-)/TSCl fx/+ showed progressive medial thicken under hypoxia, but the former was more obvious.The expression of phosphorylation of S6 (biomarker of active mTOR) gradually increased in lungs of these two genotypic mice exposed to hypoxia in the first 2 weeks, then decreased.And Tek-cre(+)/TSCl fx/+ mice showed higher amounts.Conclusion: TSC1/mTOR pathway is involved in hypoxia-induced PH in mice, which provides a novel target for PH therapy.
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