Proteome-Based Systems Biology Analysis of the Diabetic Mouse Aorta Reveals Major Changes in Fatty Acid Biosynthesis as Potential Hallmark in Diabetes Associated Vascular Disease
Background—Macrovascular complications of diabetes are a major risk factor for cardiovascular morbidity and mortality. Currently, studies only partially described the molecular pathophysiology of diabetes-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-induced key molecular changes in the vasculature. An integrative proteomic and bioinformatics analysis of data from aortic vessels in the low-dose streptozotocin (STZ)-induced diabetic mouse model (10 animals), was performed. We observed pronounced dysregulation of molecules involved in myogenesis, vascularisation, hypertension, hypertrophy (associated with thickening of the aortic wall), and a substantial reduction of fatty acid storage. A novel finding is the pronounced down-regulation of glycogen synthase kinase-3-beta Gsk3b and up-regulation of molecules linked to the TCA cycle, e.g. aspartate aminotransferase Got2 and hydroxyacid-oxoacid transhydrogenase Adhfe1. Additionally 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 over-production of ketone-bodies within the vessels using an alternative TCA-cycle associated pathway, ultimately leading to the development of atherosclerosis.
Conclusions—STZ-induced diabetes in animals leads to a reduction of fatty acid biosynthesis and an up-regulation 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.
- Received February 21, 2013.
- Revision received December 12, 2013.
- Accepted January 29, 2014.