The role of the adiponectin-adiponectin receptor pathway in human carotid atherosclerotic plaque instability

Stroke is one of the leading causes of mortality and long-term disability in Canada. Carotid atherosclerotic plaque instability is a key cause of ischemic strokes. Current guidelines recommend surgical intervention (carotid endarterectomy or carotid artery stenting) for stroke prevention based solely on the degree of carotid artery stenosis. However, stenosis alone is an incomplete determinant of a patient’s stroke risk as it does not entirely reflect how unstable a plaque truly is and its likelihood to rupture. Instead it has been increasingly recognized that plaque composition plays a critical role in defining plaque instability. Another major concern in carotid disease management is the lack of sex-specific guidelines, which has led to suboptimal prevention and treatment of strokes particularly in women. Therefore, it is imperative to identify the potential mechanisms involved in carotid plaque instability in women and in men. Adiponectin is the most abundantly secreted adipokine with vasculoprotective and anti-inflammatory properties that interacts with two transmembrane receptors, AdipoR1 and AdipoR2. A series of ex vivo and in vitro experiments were conducted in the development of this thesis. To achieve this, our large ongoing bio-bank of human carotid plaque specimens and blood samples were used to determine: (1) the contribution of the adiponectin-AdipoR pathway in carotid atherosclerotic plaque instability, (2) the effect of modulating this pathway in the monocyte-macrophage lineage, and (3) sex-specific signatures associated with the adiponectin-AdipoR pathway and plaque instability. Firstly, our results demonstrated that intraplaque expression of adiponectin plays a more important role in the context of plaque instability than circulating levels of total adiponectin. Moreover, we identified a novel association between decreased adiponectin-mediated signalling through the AdipoR2 pathway and greater plaque instability. This may impair the atheroprotective actions of adiponectin in the plaque and cause adiponectin resistance, thereby contributing to the accumulation of adiponectin observed in more vulnerable lesions. Secondly, our results contributed evidence suggesting that adiponectin may significantly improve the efficiency of the rate-limiting step of the cholesterol efflux process and promote nascent high-density lipoprotein biogenesis from macrophages via activation of both the AdipoR1 and AdipoR2 receptors. Thirdly, although statins are widely used for the primary and secondary prevention of cardiovascular disease, intensive statin therapy was found to compromise the expression and function of adiponectin and its receptors in the monocyte-macrophage lineage. Lastly, we demonstrated that men and women who underwent a carotid endarterectomy exhibit clear differences not only at the level of the plaque (i.e., plaque composition) but also at the level of the circulation (i.e., adipokine, lipid, and immune profiles). Specifically, we identified that a decrease in the high molecular-weight to total adiponectin ratio was independently associated with greater plaque instability specifically in women but not in men. Moreover, we have developed a comprehensive method to measure sex hormones using liquid chromatography-tandem mass spectrometry that will be used in the future to identify sex-specific signatures related to plaque instability in men and women. The results of these studies taken together, have provided evidence for the adiponectin-AdipoR pathway as a: (a) novel mechanism of plaque instability, (b) potential therapeutic target for plaque stabilization and ultimately, stroke prevention, and (c) probable sex-specific marker of plaque instability. Overall, our novel findings might be a stepping stone with the potential to ultimately lead to improvements in the identification, management, and treatment of ‘unstable’ carotid atherosclerosis

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