title: Activation of hypoxia response in endothelial cells contributes to ischemic cardioprotection.
abstract: Small-molecule inhibition of hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs) is being explored for the treatment of anemia. Previous studies have suggested that HIF-P4H-2 inhibition may also protect the heart from an ischemic insult. Hif-p4h-2(gt/gt) mice, which have 76 to 93% knockdown of Hif-p4h-2 mRNA in endothelial cells, fibroblasts, and cardiomyocytes and normoxic stabilization of Hif-α, were subjected to ligation of the left anterior descending coronary artery (LAD). Hif-p4h-2 deficiency resulted in increased survival, better-preserved left ventricle (LV) systolic function, and a smaller infarct size. Surprisingly, a significantly larger area of the LV remained perfused during LAD ligation in Hif-p4h-2(gt/gt) hearts than in wild-type hearts. However, no difference was observed in collateral vessels, while the size of capillaries, but not their number, was significantly greater in Hif-p4h-2(gt/gt) hearts than in wild-type hearts. Hif-p4h-2(gt/gt) mice showed increased cardiac expression of endothelial Hif target genes for Tie-2, apelin, APJ, and endothelial nitric oxide (NO) synthase (eNOS) and increased serum NO concentrations. Remarkably, blockage of Tie-2 signaling was sufficient to normalize cardiac apelin and APJ expression and resulted in reversal of the enlarged-capillary phenotype and ischemic cardioprotection in Hif-p4h-2(gt/gt) hearts. Activation of the hypoxia response by HIF-P4H-2 inhibition in endothelial cells appears to be a major determinant of ischemic cardioprotection and justifies the exploration of systemic small-molecule HIF-P4H-2 inhibitors for ischemic heart disease.
authors.affiliation: Department of Pharmacology and Toxicology, Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Risto
authors.initials: R
authors.lastname: Kerkelä
authors.forename: Sara
authors.initials: S
authors.lastname: Karsikas
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szabo
authors.forename: Raisa
authors.initials: R
authors.lastname: Serpi
authors.forename: Johanna
authors.initials: J
authors.lastname: Magga
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Andrey
authors.initials: A
authors.lastname: Anisimov
authors.forename: Raija
authors.initials: R
authors.lastname: Sormunen
authors.forename: Ilkka
authors.initials: I
authors.lastname: Pietilä
authors.forename: Laura
authors.initials: L
authors.lastname: Vainio
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Kari I
authors.initials: KI
authors.lastname: Kivirikko
authors.forename: Johanna
authors.initials: J
authors.lastname: Myllyharju
authors.forename: Peppi
authors.initials: P
authors.lastname: Koivunen
mesh_terms: D000818:Animals; D017209:Apoptosis; D015687:Cell Hypoxia; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006321:Heart / Q000503:physiopathology; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D042787:Receptor, TIE-2 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051793:Hypoxia-Inducible Factor 1; D012333:RNA, Messenger; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse