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- Reptile freeze tolerance: Metabolism and gene expression

Another of the consistent results from our screening of C. p. marginata liver and heart for freeze and anoxia responsive genes was the identification of selected serpins as up-regulated in response to stress. Array screening showed that serpin C1 (antithrombin) and D1 (heparin cofactor II; liver only) were up-regulated in liver of frozen or anoxic hatchling turtles whereas serpin G1 (complement inhibitor) was up-regulated in heart. Furthermore, anoxia exposure of adult T. s. elegans turtles also triggered enhanced expression of some serpins in liver and heart including C1 and D1 as well as F1 (also known as PEDF) which is an inhibitor of vascular endothelial growth factor [77]. Eight different serpins (including C1) were also up-regulated during hibernation in organs of ground squirrels, Spermophilus tridecemlineatus [76].

Serpins are a superfamily of proteins with 16 clades. They have a common core domain of three β-sheets and 8–9 α-helices and most are glycoproteins of 40–60 kDa [34]. The majority are plasma proteins (typically synthesized and secreted by liver) that act as irreversible covalent inhibitors of proteases that cleave specific proteins. Many inhibit the proteases that are critical checkpoints in self-perpetuating proteolytic cascades such as the proteases involved in blood coagulation, fibrinolysis, inflammation, and complement activation [34]. Elevated levels of selected serpins could be key for inhibiting specific proteolytic reactions and cascades that could otherwise cause damage to tissues over the long term in anoxic, frozen or hibernating states. One such problem is an increased risk of blood clotting. A key part of metabolic rate depression in both anaerobic turtles and hibernating mammals is a profound bradycardia whereas freezing halts circulation completely. Reduced blood flow can result in spontaneous clot formation, a common problem in states of medical ischemia. This problem in natural systems may be counteracted by the up-regulation and secretion of selected serpins into the plasma. For example, serpin C1 (antithrombin) and D1 (heparin cofactor II) both inhibit thrombin in the coagulation cascade and, thereby, also block feedback activation of the cascade by thrombin [34]. In the hatchling turtles, the net effect of up-regulation of these genes and increased production and export of these two serpins would be to reduce clotting capacity during natural freezing or anoxic excursions.

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