Death-associated protein kinase 3 mediates vascular inflammation and development of hypertension in spontaneously hypertensive rats.

Death-associated protein kinase (DAPK) is a Ca2+/calmodulin-regulated serine/threonine kinase that mediates cell death. Our recent study demonstrated that DAPK3 protein increases in the mesenteric artery from spontaneously hypertensive rats compared with Wistar Kyoto rats. Pathogenesis of hypertension is modulated at least in part by vascular inflammation. We examined whether DAPK3 mediates vascular inflammatory responses and development of hypertension. In rat mesenteric arterial smooth muscle cells, small interfering RNA against DAPK3 inhibited vascular cell adhesion molecule 1 expression and monocyte adhesion induced by tumor necrosis factor-α. DAPK3 small interfering RNA inhibited phosphorylation of c-Jun amino-terminal kinase, p38, and Akt, as well as reactive oxygen species (ROS) production induced by tumor necrosis factor-α. In human umbilical vein endothelial cells, expressions of vascular cell adhesion molecule 1, endothelial selectin, and cyclooxygenase 2, as well as ROS production induced by tumor necrosis factor-α, were inhibited by DAPK inhibitor. In vivo, blood pressure, ROS production, inflammatory molecule expression (vascular cell adhesion molecule 1 and endothelial selectin), and hypertrophy in isolated mesenteric artery were elevated in spontaneously hypertensive rats (10 weeks old), which were prevented by long-term treatment with a DAPK inhibitor (500 µg/kg per day for 6 weeks). In isolated mesenteric artery, the increased angiotensin II-induced contraction and the impaired acetylcholine-induced endothelium-dependent relaxation in spontaneously hypertensive rats were reversed by a DAPK inhibitor. The present results for the first time demonstrated in cultured smooth muscle cells and endothelial cells that DAPK3 mediates tumor necrosis factor-induced inflammatory responses via ROS-dependent mechanisms. It is also suggested that DAPK3 mediates the development of hypertension in spontaneously hypertensive rats likely via ROS-dependent inflammation, hypertrophy, and hypercontractility.