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.

Pex5p is the receptor for the peroxisomal targeting signal 1 (PTS1) that consists of a C-terminal tripeptide (consensus (S/A/C)(K/R/H)(L/M)). Hexadecapeptides recognized by Pex5p from Homo sapiens and Saccharomyces cerevisiae were identified by screening a two-hybrid peptide library, and the targeting ability of the peptides was demonstrated using the green fluorescent protein as reporter. The PTS1 receptors recognized in a speciesspecific manner a broad range of C-terminal tripeptides, and these are reported herein. In addition, residues upstream of the tripeptide influenced the strength of the interaction in the two-hybrid system as well as in an in vitro competition assay. In peptides interacting with the human protein, hydrophobic residues were found with high frequency especially at positions ؊2 and ؊5, whereas peptides interacting with S. cerevisiae Pex5p were more hydrophilic and frequently contained arginine at position ؊2. In instances where the terminal tripeptide deviated from the consensus, upstream residues exerted a greater influence on the ability of the hexadecapeptides to bind Pex5p.

Page 704, credit for the schematic panels in the model of vessel remodeling during lung maturation ( Fig. 2c-e) was omitted. The panels were originally published in Fig. 3 of Burri, P.H. Fetal and postnatal development of the lung. Annu. Rev. Physiol. 46, 617-628 (1984). This reference should be added as reference 44 on p. 710.Elsewhere on the same page, the authors erroneously used the term 'alveoli', which refers to structures that form only after birth, to denote 'saccules', which form during the saccular stage of embryonic development. In the legend of Fig. 2, the description of parts c-e should read: "c-e, Schematic illustration of capillary remodeling in septa. During lung development, capillaries around the airspaces establish a close contact with the overlying cuboidal epithelium (c). Perinatally, secondary septa develop from primary septa, containing a double capillary network (d). In the mature lung, interalveolar septa contain a single capillary layer (e)." In the body of the article, the second through fourth full sentences of the right-hand column should be replaced by the following: "In addition, capillaries in the septa failed to remodel properly in HIF-2α -/-mice. During normal lung development 44 , capillaries, which previously formed a loose network within the mesenchyme, arrange themselves around the airspaces, subsequently establishing in many places a close contact with the overlying cuboidal epithelium (Fig. 2c). During the saccular stage, the capillary networks form a capillary bilayer in the intersacullar septa as the airspaces approach each other (Fig. 2d). In the mature lung, interalveolar septa contain a single capillary layer (Fig. 2e)."

Gene transfer of PAF-AH inhibited injury-induced neointima formation and spontaneous atherosclerosis in apolipoprotein E-deficient mice. Our data indicate that PAF-AH, by reducing oxidized lipoprotein accumulation, is a potent protective enzyme against atherosclerosis.