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Role of hypoxia-inducible factor 1alpha in T cells as a negative regulator in development of vascular remodeling.

ABSTRACT: BACKGROUND AND PURPOSE: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. METHODS AND 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.

SUBMITTER: Kurobe H

PROVIDER: S-EPMC6392182 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Role of hypoxia-inducible factor 1alpha in T cells as a negative regulator in development of vascular remodeling.

Kurobe Hirotsugu H 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

Arteriosclerosis, thrombosis, and vascular biology 20091210 2

<h4>Background and purpose</h4>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.<h4>Methods and results</h4>To study the role of T cells in the development of vascular remodeling, femoral arterial injury induced by an ext ...[more]

PMID: 20007912

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Project description:BACKGROUND: Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional regulator of genes regulating oxygen homeostasis. The HIF-1 protein is composed of two HIF-1alpha and HIF-1beta/aryl hydrocarbon receptor nuclear translocator (ARNT) subunits. The prognostic relevance of HIF-1alpha protein overexpression has been shown in breast cancer. The impact of HIF-1alpha alternative splice variant expression on breast cancer prognosis in terms of metastasis risk is not well known. METHODS: Using real-time quantitative reverse transcription PCR assays, we measured mRNA concentrations of total HIF-1alpha and 4 variants in breast tissue specimens in a series of 29 normal tissues or benign lesions (normal/benign) and 53 primary carcinomas. In breast cancers HIF-1alpha splice variant levels were compared to clinicopathological parameters including tumour microvessel density and metastasis-free survival. RESULTS: HIF-1alpha isoforms containing a three base pairs TAG insertion between exon 1 and exon 2 (designated HIF-1alphaTAG) and HIF-1alpha736 mRNAs were found expressed at higher levels in oestrogen receptor (OR)-negative carcinomas compared to normal/benign tissues (P = 0.009 and P = 0.004 respectively). In breast carcinoma specimens, lymph node status was significantly associated with HIF-1alphaTAG mRNA levels (P = 0.037). Significant statistical association was found between tumour grade and HIF-1alphaTAG (P = 0.048), and total HIF-1alpha (P = 0.048) mRNA levels. HIF-1alphaTAG mRNA levels were also inversely correlated with both oestrogen and progesterone receptor status (P = 0.005 and P = 0.033 respectively). Univariate analysis showed that high HIF-1alphaTAG mRNA levels correlated with shortened metastasis free survival (P = 0.01). CONCLUSIONS: Our results show for the first time that mRNA expression of a HIF-1alphaTAG splice variant reflects a stage of breast cancer progression and is associated with a worse prognosis.See commentary: http://www.biomedcentral.com/1741-7015/8/45.

Dataset Information

Role of hypoxia-inducible factor 1alpha in T cells as a negative regulator in development of vascular remodeling.

Publications

Role of hypoxia-inducible factor 1alpha in T cells as a negative regulator in development of vascular remodeling.

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