HYPOXIC UPREGULATION OF ARGINASE II IN HUMAN LUNG ENDOTHELIAL CELLS.
Summary of "HYPOXIC UPREGULATION OF ARGINASE II IN HUMAN LUNG ENDOTHELIAL CELLS."
Activated arginase has been implicated in many diseases including cancer, immune cell dysfunction, infections, and vascular disease. Enhanced arginase activity has been reported in lungs of patients with pulmonary artery hypertension. We used hypoxia as a model for pulmonary hypertension and studied the effect of exposure to hypoxia on arginase activity in human lung microvascular endothelial cells (HMVEC). Hypoxia induces upregulation of arginase activity as well as mRNA and protein levels of arginase II (Arg II), the only arginase isoform we were able to identify in HMVEC. In endothelial cells arginase shares and competes for the substrate L-arginine with nitric oxide synthase (NOS). Through regulation of substrate availability for NOS, arginase is able to modulate nitric oxide (NO) production. To evaluate the role of Arg II in regulation of NO production under hypoxia we compared NO output (RFL-6 reporter assay) in cells with normal and silenced Arg II. Exposure to hypoxia led to an increase in NO levels produced by HMVEC. Inhibition of Arg II by specific siRNA or by the pharmacological inhibitor BEC additionally enhanced the levels of NO. Another possible role for activated arginase is involvement in regulation of cell proliferation. However, we showed that hypoxia decreased cell proliferation and upregulated Arg II did not have effect on cell proliferation. Since HIF is a family of transcriptional factors activated by hypoxia, we tested the possibility of involvement of HIF-1 and HIF-2 in regulation of Arg II under hypoxia. The silencing of HIF-2 but not HIF-1 prevented the activation of Arg II by hypoxia.
Affiliation
1University of Florida.
Journal Details
This article was published in the following journal.
Name: American journal of physiology. Cell physiology
ISSN: 1522-1563
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20861464
- DOI: http://dx.doi.org/10.1152/ajpcell.00068.2010
Medical and Biotech [MESH] Definitions
Misonidazole
A nitroimidazole that sensitizes normally radio-resistant hypoxic cells to radiation. It may also be directly cytotoxic to hypoxic cells and has been proposed as an antineoplastic.
Vascular Endothelial Growth Factor Receptor-2
A 200-230-kDa tyrosine kinase receptor for vascular endothelial growth factors found primarily in endothelial and hematopoietic cells and their precursors. VEGFR-2 is important for vascular and hematopoietic development, and mediates almost all endothelial cell responses to VEGF.
Leukotriene C4
The conjugation product of LEUKOTRIENE A4 and glutathione. It is the major arachidonic acid metabolite in macrophages and human mast cells as well as in antigen-sensitized lung tissue. It stimulates mucus secretion in the lung, and produces contractions of nonvascular and some VASCULAR SMOOTH MUSCLE. (From Dictionary of Prostaglandins and Related Compounds, 1990)
Vascular Endothelial Growth Factors
A family of angiogenic proteins that are closely-related to VASCULAR ENDOTHELIAL GROWTH FACTOR A. They play an important role in the growth and differentiation of vascular as well as lymphatic endothelial cells.
Acute Lung Injury
A condition of lung damage that is characterized by bilateral pulmonary infiltrates (PULMONARY EDEMA) rich in NEUTROPHILS, and in the absence of clinical HEART FAILURE. This can represent a spectrum of pulmonary lesions, endothelial and epithelial, due to numerous factors (physical, chemical, or biological).
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