To explain this apparent lack of specificity of expression of ET-1 requires further understanding of the regulation of ET-1 production. Circulating levels of ET-1 are elevated in patients with hypoxic lung disease and, of interest, on ascent to altitude, the plasma ET-1 levels rise in association with the fall in arterial partial pressure of oxygen.
At a cellular level, hypoxia increases ET-1 expression. The regulation of this is achieved through a sensor and can be blocked by chlorhexadine and enhanced by transitional metals. It is unlikely to be a haern moeity as it is affected by desferixamine but is not affected by inhibitors of protein kinase C or A, Ca2+ calmodulin-dependent protein kinase, or cyclic guanosine monophosphate-dependent protein kinase. Change in the cell redox status may be the trigger, and the muscle factor AP-1 appears involved.
AP-1 promotion of ET-1 expression is enhanced by GATA2. It may bind to the HIF-1 promoter site canada health and care mall. However, the most interesting finding in the study of human pulmonary artery cell cultures and artery organoid cultures is that the effect of hypoxia on ET-1 expression is hyperinduced by lipopolysaccharide, interleukin-lp, and tumor necrosis factor-a. In this preparation, in comparison to ET-1, NOS III expression is inhibited, and the effect is augmented by interleukin-1(3 and tumor necrosis factor-a.
It appears that ET-1 is the final stage of transduction of a number of pulmonary smooth muscle contractile and mitogenic factors (Fig 4). NO and PGI2 together with atrial natriuretic peptide inhibit the expression of ET-1. As the putative final step in transducing many of the procon-tractile and mitogenic factors, it should be possible to abolish these actions by reducing the amounts of ET-1 with converting enzyme inhibitors. Alternatively, the actions of ET-1 could be blocked with antagonists to ET-1 receptors.
Figure 4. Regulation of the effects of ET-1. ET = endothelin: ANP = atrial naturietic peptide.