Coronary heart diseases (CHD) remain the most prevalent cause of premature death. Ischemic hearts often result from coronary vasculature occlusion. Significant efforts have been made for the treatment of CHD, including medications and surgical procedures. Currently there are still no effective drugs or therapeutics available for the treatment of the disease. Growing new coronary vessels to naturally bypass narrowed/occluded arteries or forming sufficient collaterals to the ischemic region would lead to substantially improved blood perfusion and correction of ischemia. However, this aim remains a theoretical ideal due to the negligible ability to grow new coronary vessels even with current advances in therapeutic angiogenesis. In the present study, we have isolated and identified an active fraction of Geum japonicum (AFGJ) showing significant activity in induction of efficient coronary angiogenesis and heart function improvement. / In addition, proteomics methods were applied to investigate the protein alterations in CHD ischemic hearts and HUVECs. Two dimensional polyacrylamide gel electrophoresis (2-D PAGE) of the heart tissues of CHD rats showed 16 differentially expressed spots compared with sham and vehicle hearts, of which 8 were identified. Furthermore, 11 identified proteins of HUVECs treated with AFGJ or Angio-G at different time points were also observed by 2-D PAGE. The majority of identified proteins was found to be involved in the process of energy metabolisms. / In conclusion, these results have demonstrated therapeutic properties of AFGJ to induce early reconstitution of damaged coronary vasculature through both angiogensis and vasculogenesis. AFGJ treatments may provide a novel therapeutic modality for effective treatment of ischemic heart diseases. / The therapeutic effect of AFGJ on CHD through reconstitution of partially occluded coronary vessels in CHD animal models was demonstrated with underlying signaling mechanisms identified. Briefly, AFGJ could promote the proliferation of human umbilical vein endothelial cells (HUVECs) in vitro and the growth of new blood vessels or coronary collaterals in CHD models after 2-week treatment. The number of newly formed coronary vessels in treated hearts was more than that of vehicle treated hearts, as indicated by both MicroCT and histology analysis. Echocardiography studies demonstrated significant improvement of heart functions 2 weeks after treatment with AFGJ. Furthermore, ECG measurements showed that the altered ST segment in AFGJ treated CHD models almost had full recovery to a normal level while rats in the vehicle group consistently suffered from heart ischemia. Moreover, the results of MicroCT reconstruction directly demonstrated the reconstitution of the damaged coronary vessels with newly formed functional coronary collaterals, as illustrated by more blood vessels density (AFGJ vs vehicle [%]: 4.5+/-0.5 vs 2+/-0.35) and more branching points (AFGJ vs vehicle: 0.94+/-0.07 vs 0.65+/-0.10). These data suggest that AFGJ treatment significantly corrects the ischemia of the affected regions of the heart. / We also explored possible mechanisms underlying the effect of AFGJ. Firstly, AFGJ could induce mesenchymal stem cell (MSC) differentiation into vascular endothelial cells and the differentiated MSCs were involved in the tube formation. Secondly, Angio-G, the component derived from AFGJ, was able to stimulate significant proliferation of HUVECs in a dose dependent manner. Thirdly, in our tube-like capillary formation test of HUVECs in vitro, the length of formed tubes was greatly amplified with increasing concentration of Angio-G. Furthermore, the total length of Angio-G induced tubes was significantly reduced with increasing concentrations of AG490, an inhibitor of JAK/STAT pathways indicating possible involvement of the JAK/STAT signaling pathway. / Chen, Hao. / "December 2009." / Source: Dissertation Abstracts International, Volume: 72-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 136-145). / 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 Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_344447 |
| Date | January 2010 |
| Contributors | Chen, Hao, Chinese University of Hong Kong Graduate School. Division of Physiology. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xx, 145 leaves : ill.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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