Aragonés Julián, Schneider Martin, Van Geyte Katie, Fraisl Peter, Dresselaers Tom, Mazzone Massimiliano, Dirkx Ruud, Zacchigna Serena, Lemieux Hélène, Jeoung Nam Ho, Lambrechts Diether, Bishop Tammie, Lafuste Peggy, Diez-Juan Antonio, Harten Sarah K, Van Noten Pieter, De Bock Katrien, Willam Carsten, Tjwa Marc, Grosfeld Alexandra, Navet Rachel, Moons Lieve, Vandendriessche Thierry, Deroose Christophe, Wijeyekoon Bhathiya, Nuyts Johan, Jordan Benedicte, Silasi-Mansat Robert, Lupu Florea, Dewerchin Mieke, Pugh Chris, Salmon Phil, Mortelmans Luc, Gallez Bernard, Gorus Frans, Buyse Johan, Sluse Francis, Harris Robert A, Gnaiger Erich, Hespel Peter, Van Hecke Paul, Schuit Frans, Van Veldhoven Paul, Ratcliffe Peter, Baes Myriam, Maxwell Patrick, Carmeliet Peter
The Center for Transgene Technology and Gene Therapy, Katholieke Universiteit (K.U.) Leuven, Leuven, B-3000, Belgium.
Nat Genet. 2008 Feb;40(2):170-80. doi: 10.1038/ng.2007.62. Epub 2008 Jan 6.
HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparalpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress.
缺氧诱导因子脯氨酰羟化酶（PHD1-3）是氧传感器，以氧依赖的方式调节缺氧诱导因子（HIFs）的稳定性。在此，我们表明，Phd1的缺失通过激活过氧化物酶体增殖物激活受体α（Pparalpha）途径，将葡萄糖代谢从氧化型重编程为更多的无氧ATP生成，从而降低骨骼肌中的氧消耗。这种对氧保存的代谢适应在健康条件下会损害氧化型肌肉性能，但它能为肌纤维提供针对致命性缺血的急性保护。缺氧耐受性并非由于HIF依赖的血管生成、红细胞生成或血管舒张，而是由于氧化应激的产生减少，这使得缺乏Phd1的肌纤维能够维持线粒体呼吸。缺氧耐受性主要依赖于Hif-2alpha，在杂合Phd2缺陷或纯合Phd3缺陷小鼠中未观察到。具有医学重要性的是，Phd1的条件性敲低也能迅速诱导缺氧耐受性。这些发现阐明了Phd1在缺氧耐受性中的新作用，并为以氧化应激为特征的疾病提供了新的治疗前景。
