title: Deletion of phd2 in myeloid lineage attenuates hypertensive cardiovascular remodeling.
abstract: BACKGROUND
  Hypertension induces cardiovascular hypertrophy and fibrosis. Infiltrated macrophages are critically involved in this process. We recently reported that inhibition of prolyl hydroxylase domain protein 2 (PHD2), which hydroxylates the proline residues of hypoxia-inducible factor-α (HIF-α) and thereby induces HIF-α degradation, suppressed inflammatory responses in macrophages. We examined whether myeloid-specific Phd2 deletion affects hypertension-induced cardiovascular remodeling.
  
  
  RESULTS
  Myeloid-specific PHD2-deficient mice (MyPHD2KO) were generated by crossing Phd2-floxed mice with LysM-Cre transgenic mice, resulting in the accumulation of HIF-1α and HIF-2α in macrophage. Eight- to ten-week-old mice were given N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, and Angiotensin II (Ang II) infusion. L-NAME/Ang II comparably increased systolic blood pressure in control and MyPHD2KO mice. However, MyPHD2KO mice showed less aortic medial and adventitial thickening, and macrophage infiltration. Cardiac interstitial fibrosis and myocyte hypertrophy were also significantly ameliorated in MyPHD2KO mice. Transforming growth factor-β and collagen expression were decreased in the aorta and heart from MyPHD2KO mice. Echocardiographic analysis showed that left ventricular hypertrophy and reduced ejection fraction induced by L-NAME/Ang II treatment in control mice were not observed in MyPHD2KO mice. Administration of digoxin that inhibits HIF-α synthesis to L-NAME/Ang II-treated MyPHD2KO mice reversed these beneficial features.
  
  
  CONCLUSIONS
  Phd2 deletion in myeloid lineage attenuates hypertensive cardiovascular hypertrophy and fibrosis, which may be mediated by decreased inflammation- and fibrosis-associated gene expression in macrophages. PHD2 in myeloid lineage plays a critical role in hypertensive cardiovascular remodeling.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Ikeda
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ichiki
authors.forename: Hirohide
authors.initials: H
authors.lastname: Matsuura
authors.forename: Eriko
authors.initials: E
authors.lastname: Inoue
authors.forename: Junji
authors.initials: J
authors.lastname: Kishimoto
authors.forename: Aya
authors.initials: A
authors.lastname: Watanabe
authors.forename: Chikahiro
authors.initials: C
authors.lastname: Sankoda
authors.forename: Shiro
authors.initials: S
authors.lastname: Kitamoto
authors.forename: Tomotake
authors.initials: T
authors.lastname: Tokunou
authors.forename: Kotaro
authors.initials: K
authors.lastname: Takeda
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Fong
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000818:Animals; D002319:Cardiovascular System / Q000473:pathology*; D005355:Fibrosis / Q000209:etiology / Q000235:genetics; D017353:Gene Deletion; D006973:Hypertension / Q000150:complications*; D006984:Hypertrophy / Q000209:etiology / Q000235:genetics; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics*; D051379:Mice; D022423:Myeloid Cells
chemical_list: C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: fibrosis; hypertrophy; hypoxia; macrophages; migration