Coronary artery disease limits myocardial blood flow and results in myocardial infarction. Reperfusion therapies restore coronary flow, but may also cause myocardial ischemia reperfusion injury (MIRI). Multiple critical factors contribute to MIRI and among them, oxidative stress plays an important role. This burst of oxidative stress during reperfusion is caused by a variety of sources which collectively are called reactive oxygen species (ROS). Peroxynitrite is more cytotoxic than other ROSs, which at high concentration serves as a detrimental molecule with a variety of target. Peroxynitrite is largely produced during the early reperfusion due to the dramatically increased concentrations of superoxide (O2●-) and nitric oxide (NO). Current cardioprotective therapies against MIRI include exogenous antioxidant treatment and conditioning treatment that induced endogenous antioxidant signaling which upregulates heme oxygenase1 (HO-1), which confers its antioxidant effect in cells and tissues by degrading the latent oxidant heme and generating downstream antioxidant molecules. More importantly, peroxynitrite is closely related to HO-1 in pathogenesis of MIRI and pharmacological or genetic methods that induce over-expression of HO-1 in turn decrease the peroxynitrite generation. In this thesis we report the results of three studies designed to explore the interaction of peroxynitrite and HO-1 in cardioprotection against MIRI.
In the first study we demonstrated that HO-1 plays an essential role in chronic antioxidant treatment against MIRI in 4-week diabetic rats. Chronic antioxidant treatment with two kinds of antioxidants that target different sources of ROSs was administrated in an in vivo study with streptozotocin (STZ)-induced type 1 diabetic rats. Antioxidant treatments synergistically attenuate MIRI and cardiac dysfunction in type 1 diabetic rats by enhancing HO-1 expression, and inhibition of HO-1 expression cancelled antioxidant cardioprotection. This finding was supported by in vitro experiments in a cardiomyocyte hypoxia-reoxygenation model.
The second study explored the peroxynitrite/HO-1 interaction in propofol post-conditioning (PPC) in acute MIRI with both ex vivo and in vivo animal models. We showed that PPC conferred similar cardioprotection as an established intervention˗ischemic post-conditioning (I-PostC). PPC cardioprotection was achieved through down-regulating peroxynitrite formation and activation of HO-1 and its related signaling molecules. This finding indicates that anaesthetic post-conditioning treatment (such as PPC) can achieve similar cardioprotection as ischemic post-conditioning and can avoid potential mechanical injury that may be caused by I-PostC. Inhibition of peroxynitrite reduction and subsequent enhanced HO-1 expression may be the fundamental mechanism of PPC cardioprotection.
Lastly, we further explored PPC cardioprotection against MIRI in diabetic rats. We found that the diabetic heart lost its sensitivity to PPC and the diminished effect of PPC in inducing HO-1 over-expression may be a key mechanism. Exogenous supplementation of adiponectin, an adipocyte-derived plasma protein with anti-diabetic and anti-inflammatory properties, restored diabetic heart sensitivity to PPC that is associated with restoration of HO-1 expression. This finding may provide a potential therapy rescuing diabetic patient challenged by myocardial infarction.
The studies described in this thesis have enhanced our knowledge concerning the role of peroxynitrite in the pathogenesis of MIRI and the critical role of HO-1 in different cardioprotective therapies, in particular anaesthetic postconditioning cardioprotection. / published_or_final_version / Anaesthesiology / Doctoral / Doctor of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/193463 |
| Date | January 2013 |
| Creators | Mao, Xiaowen, 毛晓雯 |
| Contributors | Xia, Z, Vanhoutte, PMGR |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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