Role of DAPK in atherosclerosis & inflammation

Accelerated and aggressive atherosclerosis is a major cause of morbidity and mortality in diabetics, highlighting the importance of understanding the mechanisms responsible for the development of this devastating pathology. Microarray studies revealed a dramatic upregulation of expression of death associated protein kinase (DAPK) in atherosclerotic patients suggesting that this important apoptosis regulatory protein may have a role in atherosclerosis. Histochemical studies of human atheromas and aortas of ApoE−/− mice demonstrated that expression of DAPK is highly upregulated throughout the plaque. Also, in response to wire‐injury, DAPK expression rapidly increased exclusively in the medial vascular smooth muscle cell (VSMC) layer of the injured femoral arteries. In differentiating cultures of primary human coronary artery VSMC, DAPK mRNA and protein increases in parallel with other smooth muscle markers. Depletion of DAPK using siRNA does not block in vitro differentiation of VSMC, but treatment of these differentiated primary VSMCs with the inflammatory cytokines TNF and TGF‐beta results in a rapid activation of DAPK as determined by decrease in autophosphorylation. Together these findings suggest that DAPK may have an important role in maintenance of differentiated VSMC during the development of atherosclerosis.