Aside from an indirect effect of PPARgamma activation to reduce insulin resistance and to facilitate adiponectin release, PPARgamma agonist could also exert direct effects on blood vessels. I provided a first line of experimental evidence demonstrating that PPARgamma agonist rosiglitazone up-regulates the endothelin B receptor (ETBR) expression in mouse aortas and attenuates endothelin-1-induced vasoconstriction through an endothelial ET BR-dependent NO-related mechanism. ETBR up-regulation inhibits endothelin-1-induced endothelin A receptor (ETAR)-mediated constriction in aortas and mesenteric resistance arteries, while selective ETBR agonist produces endothelium-dependent relaxations in mesenteric resistance arteries. Chronic treatment with rosiglitazone in vivo or acute exposure to rosiglitazone in vitro up-regulate the ETsR expression without affecting ETAR expression. These results support a significant role of ETBR in contributing to the increased nitric oxide generation upon stimulation with PPARgamma agonist. This study provides additional explanation for how PPARgamma activation improves endothelial function. / Firstly, I demonstrated that adipocyte-derived adiponectin serves as a key link in PPARgamma-mediated amelioration of endothelial dysfunction in diabetes. Results from ex vivo fat explant culture with isolated arteries showed that PPARgamma expression and adiponectin synthesis in adipose tissues correlate with the degree of improvement of endothelium-dependent relaxation in aortas from diabetic db/db mice. PPARgamma agonist rosiglitazone elevates the adiponectin release and restores the impaired endothelium-dependent relaxation ex vivo and in vivo, in arteries from both genetic and diet-induced diabetic mice. The effect of PPARgamma activation on endothelial function that is mediated through the adiponectin- AMP-activated protein kinase (AMPK) cascade is confirmed with the use of selective pharmacological inhibitors and adiponectin -/- or PPARgamma+/- mice. In addition, the benefit of PPARgamma activation in vivo can be transferred by transplanting subcutaneous adipose tissue from rosiglitazone-treated diabetic mouse to control diabetic mouse. I also revealed a direct effect of adiponectin to rescue endothelium-dependent relaxation in diabetic mouse aortas, which involves both AMPK and cyclic AMP-dependent protein kinase signaling pathways to enhance nitric oxide formation accompanied with inhibition of oxidative stress. These novel findings clearly demonstrate that adipocyte-derived adiponectin is prerequisite for PPARgamma-mediated improvement of endothelial function in diabetes, and thus highlight the prospective of subcutaneous adipose tissue as a potentially important intervention target for newly developed PPARgamma agonists in the alleviation of diabetic vasculopathy. / To summarize, the present investigation has provided a few lines of novel mechanistic evidence in support for the positive roles of PPARgamma and PPARdelta activation as potentially therapeutic targets to combat against diabetic vasculopathy. / Type 2 diabetes mellitus and obesity represent a global health problem worldwide. Most diabetics die of cardiovascular and renal causes, thus increasing the urgency in developing effective strategies for improving cardiovascular outcomes, particularly in obesity-related diabetes. Recent evidence highlights the therapeutic potential of peroxisome proliferators activated receptor (PPAR) agonists in improving insulin sensitivity in diabetes. / While agonists of PPARalpha and PPARgamma are clinically used, PPARdelta is the remaining subtype that is yet to be a target for current therapeutic drugs. Little is available in literature about the role of PPARdelta in the regulation of cardiovascular function. The third part of my thesis focused on elucidating cellular mechanisms underlying the beneficial effect of PPARdelta activation in the modulation of endothelial function in diabetes. PPARdelta agonists restore the impaired endothelium-dependent relaxation in high glucose-treated aortas and in aortas from diabetic db/db mice through activation of a cascade involving PPARdelta, phosphatidylinositol 3-kinase, and Akt. PPARdelta activation increases Akt and endothelial nitric oxide synthase and nitric oxide production in endothelial cells. The crucial role of Akt is confirmed by selective pharmacological inhibitors and transient transfection of dominant negative Akt plasmid in these cells. Treatment with PPARdelta agonist GW501516 in vivo augments endothelial function in diabetic db/db and diet-induced obese mice. The specificity of GW501516 for PPARdelta is proven with the loss of its effect against high glucose-induced impairment of endothelium-dependent relaxation in aortas from PPARdelta knockout mice. In addition, oral administration of GW501516 in vivo fails to improve endothelial function in diet-induced obese PPARdelta deficient mice. / Tian, Xiaoyu. / Adviser: Huang Yu. / Source: Dissertation Abstracts International, Volume: 73-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 132-165). / 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.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_344775 |
| Date | January 2011 |
| Contributors | Tian, Xiaoyu., 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 (xxi, 165 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/) |
Page generated in 0.0027 seconds