Abstract P810: Dysregulation of Dipeptidyl Peptidase and Adipokines in Atherosclerosis and Ischemic Stroke

Abstract

Introduction: Atherosclerosis and stroke remain the leading causes of death and functional disabilities. Stable carotid atherosclerosis (CA) plaques can rupture inducing ischemic stroke and functional impairment. However, there are gaps in our understanding of the molecular factors in cerebro-vascular diseases. Methods: Using pre-clinical animal models of atherosclerosis and ischemic stroke, we investigated the association of specific proteases and adipokines using cellular, molecular, proteomic, and biochemical approaches. We analyzed blood, brain, and aortic tissues obtained from wildtype, normal and high fat diet fed APO-E deficient mice with and without plaques, and . We examined the differential expression of levels of DPPIV and adipokines in plasma using a targeted proteome profiler antibody array. The levels of mRNA were assessed in APOE-/- aortic and brain tissues using pathway specific PCR arrays. Results: In a pre-clinical animal model of focal ischemic stroke, we found that DPPIV is significantly increased in the ischemic brain. Genetic ablation of DPPIV gene, decreased the ischemic brain infarct size in a middle cerebral artery occlusion induced ischemic mouse model. Furthermore, we observed upregulation of DPPIV expression in aortic root lesions and carotid arteries of atherogenic apolipoprotein E deficient (ApoE-/-) mice as compared to wild type animals. Circulating DPPIV levels in plasma were also significantly higher in ApoE-/- and stroke induced animals. In the plaque tissue, DPPIV was over-expressed in macrophages as indicated by its co-localization with Mac-2, and in endothelial cells (EC). Oxygen glucose deprivation induced in vitro ischemia also upregulated DPPIV expression in macrophages and EC. DPPIV decreased EC viability/mitochondrial potential, and disrupted endothelial function as shown by impaired pro-angiogenic structure formation. DPPIV expression was associated with increased levels of apoptotic and inflammatory adipokines/cytokines. Conclusion: DPPIV and adipokine dysregulation is associated with atherosclerosis and ischemic stroke. Imbalanced production of these factors may further worsen post-stroke outcome, and are potential targets for clinical intervention.