Role of hypoxia-inducible factor 1alpha in T cells as a negative regulator in development of vascular remodeling.
OBJECTIVE
Recent studies have shown that the cellular immune response in the development of vascular remodeling modulates the resulting pathological alterations. We show that hypoxia-inducible factor 1 (Hif-1) (specifically expressed in T cells) is involved in the immune response to vascular remodeling that accompanies arteriosclerosis.


RESULTS
To study the role of T cells in the development of vascular remodeling, femoral arterial injury induced by an external vascular polyethylene cuff was examined in mice lacking Hif-1 (specifically in T cells). We found that cuff placement caused prominent neointimal hyperplasia of the femoral artery in Hif-1- (T-cell)-deficient mice compared with that in control mice and that infiltration of inflammatory cells at the adventitia was markedly increased in the mutant mice. Studies to clarify the mechanism of augmented vascular remodeling in the mutant mice showed enhanced production of cytokines by activated T cells and augmented antibody production in response to a T-dependent antigen in the mutant mice.


CONCLUSIONS
The results of this study revealed that Hif-1alpha in T cells plays a crucial role in vascular inflammation and remodeling in response to cuff injury as a negative regulator of T cell-mediated immune response. Potential new therapeutic strategies that target Hif-1alpha are described.
Kurobe
Hirotsugu
H
epartment of Cardiovascular Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Urata
Masahisa
M
Ueno
Masaki
M
Ueki
Masaaki
M
Ono
Shiro
S
Izawa-Ishizawa
Yuki
Y
Fukuhara
Yayoi
Y
Lei
Yu
Y
Ripen
Adiratna Mat
AM
Kanbara
Tamotsu
T
Aihara
Ken-ichi
K
Ishizawa
Keisuke
K
Akaike
Masashi
M
Gonzalez
Frank J
FJ
Tamaki
Toshiaki
T
Takahama
Yousuke
Y
Yoshizumi
Masanori
M
Kitagawa
Tetsuya
T
Tomita
Shuhei
S
D000818:Animals; D000917:Antibody Formation; D001161:Arteriosclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000276:immunology / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D006965:Hyperplasia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007111:Immunity, Cellular; D007150:Immunohistochemistry; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009593:Nitroimidazoles / Q000008:administration & dosage; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology; D013997:Time Factors; D017539:Tunica Intima / Q000276:immunology / Q000293:injuries / Q000378:metabolism* / Q000473:pathology
D054377:Chemokine CXCL12; D016207:Cytokines; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009593:Nitroimidazoles; D011948:Receptors, Antigen, T-Cell; C033815:pimonidazole