TRAIL: A Link between Inflammation, Insulin Resistance and Vascular Complications

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Copyright: Harith, Hanis
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Abstract
Type-2 diabetes and cardiovascular disease (CVD) are commonly associated, and greatly increase mortality risk. Insulin resistance and inflammation underlie these clinical conditions. Tumour necrosis factor-related apoptosis inducing ligand (TRAIL) is a molecule implicated to play a protective role in CVD and diabetes. Given its complex signalling, TRAIL’s physiological and pathological roles are not fully elucidated. This thesis investigated the relationship between basal TRAIL gene deficiency alone and high fat diet (HFD)-induced insulin resistance, and the link between TRAIL, inflammation and insulin resistance in blood vessels, using wildtype and TRAIL knock-out mice. The role of TRAIL in diabetes-associated atherosclerosis was investigated by assessing the effects of supraphysiological concentrations of insulin and glucose on TRAIL transcriptional regulation, gene expression and cell proliferation in vascular smooth muscle cells (VSMC), the main cellular component of the vessel wall. VSMC proliferation is a key process in atherogenesis, yet it promotes plaque stability in advanced atherosclerosis. This thesis demonstrates that: i) circulating TRAIL levels are reduced in response to a HFD in wildtype mice, yet vascular TRAIL expression is upregulated, ii) TRAIL deficiency promotes whole-body, skeletal muscle and vascular insulin resistance, which are exacerbated by a HFD, iii) vascular protective effect of TRAIL in the setting of HFD-induced diabetes is associated with TRAIL’s anti-inflammatory activity, iv) both acute hyperinsulinemia and hyperglycemia positively regulate specificity protein 1 (Sp1)-mediated TRAIL transcription and gene expression in VSMC, with only insulin having the ability to promote VSMC proliferation in a TRAIL-dependent manner, and v) hyperinsulinemia-inducible TRAIL gene expression is time-dependent; chronic treatment downregulates TRAIL gene expression in VSMC. This thesis provides novel insights into the role of TRAIL in modulating insulin sensitivity, inflammation, and VSMC phenotype. TRAIL may mediate pro-atherogenic effects of hyperinsulinemia early in type-2 diabetes, whilst enhancing plaque stability in patients with advanced atherosclerosis. Thus, therapeutic effects of TRAIL in these settings may be dependent on the stage of disease.
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Author(s)
Harith, Hanis
Supervisor(s)
Kavurma, Mary
Khachigian, Levon
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Publication Year
2015
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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