Streptozotocin-induced diabetes in mice led to a reduction of fatty acid biosynthesis and an upregulation of an alternative ketone-body formation pathway in aortic vessels.
BACKGROUND: Macrovascular complications of diabetes mellitus are a major risk factor for cardiovascular morbidity and mortality. Currently, studies only partially described the molecular pathophysiology of diabetes mellitus-associated effects on vasculature. However, better understanding of systemic effects is essential in unraveling key molecular events in the vascular tissue responsible for disease onset and progression. METHODS AND RESULTS: Our overall aim was to get an all-encompassing view of diabetes mellitus-induced key molecular changes in the vasculature. An integrative proteomic and bioinformatics analysis of data from aortic vessels in the low-dose streptozotocin-induced diabetic mouse model (10 animals) was performed. We observed pronounced dysregulation of molecules involved in myogenesis, vascularization, hypertension, hypertrophy (associated with thickening of the aortic wall), and a substantial reduction of fatty acid storage. A novel finding is the pronounced downregulation of glycogen synthase kinase-3β (Gsk3β) and upregulation of molecules linked to the tricarboxylic acid cycle (eg, aspartate aminotransferase Got2 and hydroxyacid-oxoacid transhydrogenase Adhfe1). In addition, pathways involving primary alcohols and amino acid breakdown are altered, potentially leading to ketone-body production. A number of these findings were validated immunohistochemically. Collectively, the data support the hypothesis that in this diabetic model, there is an overproduction of ketone-bodies within the vessels using an alternative tricarboxylic acid cycle-associated pathway, ultimately leading to the development of atherosclerosis. CONCLUSIONS: Streptozotocin-induced diabetes mellitus in animals leads to a reduction of fatty acid biosynthesis and an upregulation of an alternative ketone-body formation pathway. This working hypothesis could form the basis for the development of novel therapeutic intervention and disease management approaches.
Husi et al. (Thu,) conducted a other in Diabetes mellitus-associated vascular disease (n=10). Streptozotocin-induced diabetes mellitus was evaluated on Molecular changes in the vasculature (proteomic and bioinformatics analysis). Streptozotocin-induced diabetes in mice led to a reduction of fatty acid biosynthesis and an upregulation of an alternative ketone-body formation pathway in aortic vessels.
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