Authors: Tipoe, George L.; Y.-H. Lau, Thomas; Nanji, Amin A.; Fung, Man-Lung

Source: Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents), Volume 4, Number 3, July 2006 , pp. 199-218(20)

Publisher: Bentham Science Publishers

Abstract:

The aims of the present review are to summarize and to discuss the role of hypoxia-inducible factor-1 (HIF-1) and the expression and functions of vasoactive substances in chronic hypoxemia with specific focus in the liver and the carotid body. Vascular remodelling and vasoactive substances play important functional roles in the adaptive response to chronic hypoxemia for the maintenance of oxygen homeostasis in all systems in man. HIF-1 regulates the gene expression of vasoactive substances such as vascular endothelial growth factor (VEGF), endothelin-1 (ET-1) and enzymes for producing nitric oxide (NO). Recent studies have shown the effect of chronic hypoxia on the expression of HIF-1α and HIF-1-target genes in multiple organ systems including the liver and the carotid body. Results are consistent with increases in the hematocrit levels, pulmonary arterial pressure and right heart mass developed during chronic hypoxia. In addition, the carotid body is also hyperplastic and increases in organ mass with increased levels of HIF-1α and the vasoactive substances. These molecules increase the mitotic activity and modulate the excitability of the chemoreceptor. Intriguingly, the liver morphology, serum alanine aminotransferase and 8-isoprostane levels are within normal range in chronic hypoxia, suggesting the absence of significant oxidative stress. Yet, the HIF-1α is upregulated and the mRNA and protein levels of VEGF, ET-1, inducible and constitutive NO synthases are elevated in the liver during chronic hypoxia. In conclusion, the adaptive response to long-term hypoxemia involves compensatory mechanisms mediated by expressing significant levels of HIF-1α and vasoactive substances regulated by HIF-1.

Keywords: Chronic hypoxia; endothelin; HIF; nitric oxide; VEGF

Document Type: Research article

DOI: http://dx.doi.org/10.2174/187152506777698290

Affiliations: 1: Department of Physiology,Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road,Pokfulam, Hong Kong SAR, China.

Publication date: 2006-07-01

More about this publication?

• Cardiovascular & Hematological Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of new Cardiovascular & Hematological Agents. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of current topics in Cardiovascular & Hematological medicinal chemistry.
  
  Cardiovascular & Hematological Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in cardiovascular & hematological drug discovery.

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