Essay: Urotensin II (U-II)

Urotensin II (U-II), a potent mammalian vasoconstrictor peptide, was initially isolated and characterized from the Gillichthys mirabilis (goby) urophysis (Pearson et al., 1980). Later, human U-II cDNA was cloned, and hU-II appeared as an eleven amino acid peptide with cysteine residues in positions 5 and 10, forming a disulfide bridge through their side chains (Coulouarn et al., 1998). The most prominent effects of U-II are observed in the mammalian cardiovascular arterial system in which it was frequently identified as the most potent vasoconstrictor. Douglas et al. (2000a) investigated the vasoconstricting effect of human U-II (hU-II) showing that both potency and efficacy varied significantly between species, individuals, and vessels. As such, hU-II was described as the most potent vasoconstricting compound on the rat thoracic aorta, but in mouse, whatever vessels were tested, no vasoconstriction was recorded. On the other hand, hU-II was a potent vasoconstrictor on nonhuman primate arteries (Ames et al., 1999; Douglas et al., 2000b). Abdominal and small pulmonary arteries showed a potent vasodilation to hU-II in presence of endothelium (Stirrat et al., 2001). Additional in vitro studies have shown that hU-II is a potent inotropic agent on human cardiac muscle (Russell et al., 2001) and that it induces vascular smooth muscle cell (VSMC) proliferation (Watanabe et al., 2001). Especially in VSMC, U-II induced signaling via U-II receptor is well characterized. After ligand binding, the Gq protein coupled receptor activates the PLC-PKC cascade, thereby inducing Ca2+ mobilization and calmodulin/MLC kinase mediated contraction. Furthermore, RhoA and MAPK signaling contribute to VSMC contraction and cell proliferation (Tasaki et al., 2004, 2002; Sauzeau et al., 2001, Iglewski et al., 2010). In vivo reports regarding U-II vascular effects appeared inconclusive since two independent studies using identical procedure showed opposite results (B??hm and Pernow, 2002; Wilkinson et al., 2002). Nevertheless, the potency of hU-II as a vasoconstricting, vasodilating, or inotropic agent strongly suggests a key role of this peptide in the cardiovascular homeostasis.
These observations are well matched with the hypothesis that U-II might be involved in various diseases, including cardiovascular pathologies such as hypertension and arteriosclerosis. Thus, the U-II biological system exhibits a remarkable potential for the development of novel therapeutic strategies, especially those related to the treatment of cardiovascular diseases. Such developments require a precise knowledge of the pharmacophoric elements within U-II that are essential for affinity and activity of this peptide. So far, because of its resemblance to somatostatin (SST), it is conceivable that some of the critical structural features already described for SST are shared with U-II. Accordingly, both peptides contain the tripeptide Phe, Trp, Lys followed by the hydroxylated residue Thr or Tyr. Moreover, it was demonstrated in SST that an interaction between the aromatic moieties of residues Phe-6 and Phe-11 stabilizes the orientation of residues Phe-7, Trp-8, Lys-9, and Thr-10. Correspondingly/Similarly, the disulfide bridge in U-II would act in a similar manner. Structure-activity relationship (SAR) studies of SST already showed that these pharmacophoric features are essential for the SST biological activity (Janecka et al., 2001). Furthermore, previous fish U-II (Itoh et al., 1987) and human U-II (Kinney et al., 2001, 2002; Flohr et al., 2002) SAR studies showed that the highly conserved C-terminal segment CFWKYCV is the minimal sequence required to maintain a high potency and that Lys-8 appeared as an important residue for U-II activity (Carmada et al., 2002). In addition, substitution of the U-II disulfide bridge with lactam bridges of various lengths showed that the biological activity of U-II is dependent upon the size of the cyclic structure (Grieco et al., 2002). Also another study reported the importance of the ring structure for U-II functional activity (Odagami et al., 2009). However, a systematic and detailed substitution analysis of U-II has not been published.

Source: Essay UK - https://www.essay.uk.com/essays/science/essay-urotensin-ii-u-ii/


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