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Novel roles of macrophage migration inhibitory factor and platelets in post-infarct cardiac inflammatory responses

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thesis
posted on 2017-01-31, 05:18 authored by Yang Liu
There is substantial evidence to suggest that inflammation plays a pivotal role in the ischemic heart disease contributing to myocardial injury and ventricular remodeling. Thus, inflammatory responses following myocardial ischemia or infarction need to be controlled. However, recent clinical trials testing anti-inflammatory interventions have been unsuccessful reflecting the urgent need for a better understanding of the inflammatory process, more suitable therapeutic targets and safe but effective regimens. Two factors have been selected as the research focus of this thesis: macrophage migration inhibitory factor (MIF) and platelets. MIF has been well known to mediate inflammatory process in a range of non-cardiovascular inflammatory diseases with recent emerging evidence indicating its role in contributing arterial atherosclerosis. In addition to hemostatic and thrombotic actions, platelets have recently been shown to promote inflammation. However, the current understanding on the role of platelets is limited to vascular actions (i.e. atherosclerosis and thrombosis). Mouse models of ischemia/reperfusion (I/R) and myocardial infarction (MI) were used to simulate ischemic heart disease in humans. To study the role of MIF in post-I/R cardiac injury, mice disrupted of MIF gene (MIF-KO) were subjected to a 60 min period of ischemia followed by reperfusion. Compared with wild-type controls, MIF-KO mice exhibited smaller infarct size, less cardiomyocyte apoptosis and better preservation of contractile function. Deletion of MIF suppressed TLR-4 signalling as well as cardiac inflammatory responses. Importantly, the infarcted myocardium from MIF-KO mice preserved a greater capacity of fatty acid oxidization following a prolonged I/R injury, action associated with a reduced glucose uptake. Collectively, these findings suggest MIF as a key cytokine exacerbating post-I/R cardiac injury and inflammation. In mice subjected to MI by permanent coronary artery occlusion, accumulation of platelets within the infarcted myocardium was observed, a temporal process closely associated with regionally infiltrated leukocytes, particularly monocytes or macrophages. Meanwhile, early after MI, there was an increased conjugation rate of platelet-leukocytes (particularly monocytes) in circulating blood, which was largely mediated by P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1). Further, monocytes that conjugated with platelets displayed a greater pro-inflammatory activity following acute MI. Notably, anti-platelet interventions by ADP receptor antagonist or platelet depletion significantly suppressed the extent of inflammation in the infarct myocardium, including a reduced tissue content of MIF, inhibited platelet-leukocyte conjugation and the proportion of P-selectin positive platelets in the peripheral blood. Clopidogrel therapy reduced the incidence of ventricular rupture in the acute phase and mitigated ventricular remodeling in the chronic phase of MI, complications closely related to regional inflammation. Preliminary experiment also confirmed the elevated platelet-monocyte conjugation in circulating blood from patients with acute MI. These findings have established the role of both MIF and platelets as key inflammation-promoting factors in the setting of ischemic heart disease. These studies also presented proof-of-concept evidence for cardiac protection via inactivation of MIF or anti-platelet therapy and indicate novel cellular or molecular candidates as therapeutic targets against post-MI inflammation. While these findings were made in the murine models, their clinical relevance is indicated by preliminary experiments on human patients with acute MI. Further clinical studies would be important to evaluate the clinical relevance of our experimental findings and to assess anti-MIF or anti-platelet therapy through inhibition of systemic and cardiac inflammation in ischemic heart disease.

History

Principal supervisor

Xiao-Jun Du

Additional supervisor 1

Xiao-Ming Gao

Year of Award

2011

Department, School or Centre

Baker IDI Heart and Diabetes Research Institute, Medicine

Campus location

Australia

Course

Doctor of Philosophy

Degree Type

DOCTORATE

Faculty

Faculty of Medicine Nursing and Health Sciences

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    Faculty of Medicine, Nursing and Health Sciences Theses

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