Abstract Th0005: Up-regulation of pyruvate kinase 2 and serine dehydratase in human aortic atherosclerosis and aneurysm

Introduction: Aortic atherosclerotic aneurysm develops asymptomatically with gradual progression and suddenly become symptomatic rupture. Inflammation is a fundamental pathophysiology of atherogenesis and aneurysmal formation. Altered vascular cell metabolism closely links to cellular function in atherosclerotic lesions. Pyruvate is an intermediate metabolite involved in both the glycolytic and tricarboxylic acid cycles. However, expression of pyruvate-synthesizing enzymes, pyruvate kinase (PKM)2 and serine dehydratase (SDS), in human aortic atherosclerosis remains unknown. Hypothesis: We hypothesized that PKM2 and SDS are localized and up-regulated in lesional cells in aortic atherosclerosis, and that the enzymes affect aortic inflammation involved in aortic aneurysm formation. Methods: We examined aortic vascular samples underwent vascular surgery as atherosclerotic aortic aneurysm, histologically classified into early (n=10 to11), advanced (n=8 to 9), aneurysmal (n=11) lesions, and compared the expression of PKM2 and SDS using qPCR and immunohistochemistry. We examined effect of PKM2 and SDS on gene expression related on inflammation and tissue remodeling (Monocyte chemotactic protein-1, IL-1β, IL-6, TGF-β, MMP9) in inflammatory stimulated human peripheral blood-mononuclear cell derived macrophages (n=12 to 20 in each group). Results: The mRNA expression of PKM2 and SDS were higher in the aortic advanced and aneurysmal lesions than those in the early lesions. The immunoreaction for PKM2 was observed mainly in macrophages, a part of smooth muscle cells, and B cells. The immunoreaction for SDS was predominantly in macrophages. TNFα and IFNγ stimuli increased PKM2 and SDS expression in the cultured macrophages. PKM2 reduction by PKM2 siRNA significantly enhanced Monocyte chemotactic protein-1 expression and reduced TGF-β expression in the cultured macrophages. SDS reduction by SDS siRNA did not affect the inflammatory and tissue remodeling gene expression. Conclusions: PKM2 and SDS were predominantly expressed in macrophages in aortic advanced and aneurysmal lesions. The upregulation of the enzymes may occur before aortic aneurysmal formation. PKM2 in macrophage may have an inhibitory effect on inflammation.