Abstract
Background: Cardiovascular disease is the leading cause of death worldwide and is responsible for three out of four deaths in diabetic individuals. Our lack of understanding of the molecular mechanisms linking diabetes and atherosclerosis impedes the development of effective treatment strategies. Hyperglycemia and glucosaminesupplementation have been shown to induce endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR) in murine models of atherosclerosis. We hypothesize that diabetes/hyperglycemia promotes atherosclerosis by a mechanism involving glucosamine-induced ER stress/UPR activation and that attenuation of ER stress, using the chemical chaperone 4- phenylbutyric acid (4PBA), will slow the accelerated development of atherosclerosis. Methods: Hyperglycemia was induced in female Apolipoprotein E-deficient (ApoE-/-) mice by multiple low-dose streptozotocin injections or by the introduction of the Ins2+/Akita mutation. Glucosamine-supplementation was achieved by adding different concentrations of glucosamine (0.625-5% w/v) to the drinking water of ApoE-/- mice. Subsets of mice from each group were also treated with 4PBA. The development of atherosclerosis was evaluated based on atherosclerotic lesion area and volume at the aortic sinus. Levels of protein O-linked N-acetylglucosamine (O-GlcNAc) and ER stress markers were determined in atherosclerotic lesions using immunohistochemistry and immunofluorescence staining. Results: Hyperglycemic and glucosamine-supplemented mouse models showed similar increases in O-GlcNAc and ER stress/UPR activation levels in atherosclerotic lesions. Lesion area was not significantly different between the three models of accelerated atherosclerosis. Glucosamine supplementation at ≥ 2.5% (w/v) significantly increased lesional O-GlcNAc, UPR activation and atherosclerotic lesion area/volume, independent of changes in any measured metabolic parameters. 4PBA mitigated ER stress and attenuated accelerated atherosclerosis in both hyperglycemic and glucosamine-supplemented mouse models. Conclusion: These findings suggest that hyperglycemia promotes accelerated atherosclerosis by a mechanism involving glucosamine-induced ER stress. Accelerated atherosclerosis can be attenuated in hyperglycemic ApoE-/- mice by reducing ER stress levels.
Highlights
Cardiovascular disease (CVD) is the leading cause of death worldwide [1]
In an attempt to understand the pro-atherogenic effects of hyperglycemia, most of the research has been focussed on determining the pathways affected by the increase in glucose metabolism and the oxidative stress associated with the hyperglycemia [10,11]
The objective of this study is to investigate the role of glucosamineinduced endoplasmic reticulum (ER) stress/unfolded protein response (UPR) activation in diabetic atherosclerosis
Summary
Cardiovascular disease (CVD) is the leading cause of death worldwide [1]. Risk factors of CVD include obesity [2], dyslipidemia [3], smoking [4], hypertension [5] and diabetes mellitus [6]. CVD is responsible for approximately 75% of deaths in individuals with diabetes [9], the development of therapeutic strategies to prevent and/or treat CVD has been impeded due to the lack of understanding of the underlying biochemical mechanisms linking diabetes to CVD. Cardiovascular disease is the leading cause of death worldwide and is responsible for three out of four deaths in diabetic individuals. Our lack of understanding of the molecular mechanisms linking diabetes and atherosclerosis impedes the development of effective treatment strategies. We hypothesize that diabetes/hyperglycemia promotes atherosclerosis by a mechanism involving glucosamine-induced ER stress/UPR activation and that attenuation of ER stress, using the chemical chaperone 4- phenylbutyric acid (4PBA), will slow the accelerated development of atherosclerosis
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