Thesis--M. Phil., University of Hong Kong, 1978. / Typewritten.

published_or_final_version / Zoology / Master / Master of Philosophy

Urotensin-II (U-II) and its receptor UT are upregulated in the pathological setting of various cardiovascular diseases including atherosclerosis. However, their exact role in atherosclerosis remains to be determined. In the present study, we hypothesized that selective overexpression of UT in an SMC-specific fashion would increase atherosclerotic lesion formation in a hypercholesterolemic mouse model. The objectives were to demonstrate the role of UT in this mouse model of atherosclerosis, and to elucidate some of the mechanism involved in the process. We used four strains of mice; wildtype (WT), UT+ (a transgenic strain expressing human UT driven by the alpha-SM22 promoter), ApoE knockout (ko), and UT+/ApoE ko. All animals were fed a high-fat diet for 12 weeks. Western blot analysis revealed a significant increase in UT expression in UT+ and ApoE ko mice (P<0.05). Serum cholesterol and triglyceride levels were significantly increased in ApoE ko and in UT+/ApoE ko but not in UT + mice when compared to wild type mice (P<0.0001). Analysis of aortas showed a significant increase in atherosclerotic lesion in the UT +, ApoE ko and UT+/ApoE ko compared to WT mice (P<0.05). Oral administration of the UT receptor antagonist SB-657510A for 10 weeks in a group of ApoE ko mice fed a high fat diet resulted in a significant reduction of lesion (P<0.001). Immunohistochemistry revealed the presence of strong expression of UT and U-II proteins in the atheroma of UT+, ApoE ko and UT+/ApoE ko mice, particularly in foam cells. SB-657510A also significantly reduced ACAT-1 protein expression in the atherosclerotic lesion of ApoE ko mice (P<0.05). The present findings suggest that the use of UT receptor antagonists may reduce lesion formation through reduced foam cell formation and lipid uptake, demonstrating an important role for UT in the pathogenesis of atherosclerosis.

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In the present study using zebrafish as the model organism, we have investigated the function of UII/UII-receptor (UIIR) signaling pathway during early embryogenesis. Herein we presented five lines of evidence supporting the hypothesis that UII/ UIIR signaling pathway is required for normal determination of asymmetric axis during early embryogenesis. First, function-loss of UII results in a concordant randomization of viscus asymmetries in embryos, including abnormalities in cardiac looping and positioning of visceral organs. Second, knockdown of UII randomizes the left-sided expression of asymmetrical genes including lefty2, spaw and pitx2c in the lateral plate mesoderm (LPM) and bmp4 in the developing heart domain and the LPM. Third, reduced UII levels interfere with the normal organogenesis of Kupffer's vesicle (KV), an organ implicated in the early steps of left-right (L-R) patterning of embryos. Fourth, repression of UII function perturbs the asymmetrical distribution of free Ca2+ (intracellular Ca2+) at the region surrounding embryo KV during early somitogenesis, which is one of the signaling mechanisms that propagandize and amplify the early clue of left-right (L-R) asymmetry. Fifth, depressing UII levels alters the normal pattern of Bmp and Nodal signaling, which modulate the establishment of L-R axis of developmental embryo. Collectively, these observations support a model in which UII/UIIR signal system takes part in the early molecular events of L-R asymmetry patterning of embryo by modulating Bmp and Nodal signaling, regulating KV normal morphogenesis, so then, maintaining the asymmetrical distribution of free intracellular Ca2+ at the peripheral region surrounding embryo KV. This study documents a role of UII/UIIR signaling pathway in the establishment of L-R axis of embryos which promises to reveal the molecular mechanisms responsible for human congenital diseases with heterotaxy. / Urotensin II (UII) is the most potent vasoconstrictor identified so far. This cyclic peptide stimulates its G protein-coupled receptor (GPR) to modulate cardiovascular system function in humans and in other animal species. / Li, Jun. / Advisers: Christopher HK Cheng; Mingliang He. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 143-168). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.