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Abstract. Neovascularization occurring in atherosclerotic plaque leads to acceleration of plaque growth through increased leukocyte infiltration and reactive oxygen species (ROS) production. Sema4D (CD100), a class IV semaphorin, not only plays a crucial role in axon guidance but also functions in the neovascularization process of tumor growth. To clarify the roles of Sema4D in the progression of atherosclerosis and neovascularization of atherosclerotic plaque, we analyzed the effect of Sema4D gene deletion from apolipoprotein E (ApoE)-deficient mice in the development of atherosclerosis. Lipid staining demonstrated significant decreases in plaque areas in the aortas of 6-month-old Sema4D -/-ApoE -/-mice compared with 6-month-old ApoE -/-mice. Thus, the Sema4D gene knockout in ApoE-deficient mice was found to slow the progression of atherosclerosis. Immunohistochemical analyses confirmed the expression of Sema4D protein in infiltrating lymphoid cells in atherosclerotic plaque and plexin-B1 receptor in neovascular endothelial cells within the plaque. Furthermore, there were significant decreases in the degree of neovascularization in the plaque areas of Sema4D -/-ApoE -/-mice compared with ApoE -/-mice as revealed by both isolectin B4 and CD31 staining. The number of infiltrating macrophages in Sema4D -/-ApoE -/-mice plaques was also significantly less than those in ApoE -/-mice. These findings suggest that Sema4D is involved in the progression phase of atherosclerosis by accelerating intimal neovascularization, resulting in enhanced macrophage infiltration in atherosclerotic plaques.

Abstract. Death-associated protein kinase (DAPK) is a calcium/calmodulin-dependent serine/threonine kinase localized to renal tubular epithelial cells. To elucidate the contribution of DAPK activity to apoptosis in renal ischemia-reperfusion (IR) injury, wild-type (WT) mice and DAPK-mutant mice, which express a DAPK deletion mutant that lacks a portion of the kinase domain, were subjected to renal pedicle clamping and reperfusion. After IR, DAPK activity was elevated in WT kidneys but not in mutant kidneys (1785.7 Ϯ 54.1 pmol/ min/mg versus 160.7 Ϯ 60.6 pmol/min/mg). Furthermore, there were more TUNEL-positive nuclei and activated caspase 3-positive cells in WT kidneys than in mutant kidneys after IR (24.0 Ϯ 5.9 nuclei or 9.4 Ϯ 0.6 cells per high-power field [HPF] versus 6.3 Ϯ 2.2 nuclei or 4.4 Ϯ 0.7 cells/HPF at 40 h after ischemia). In addition, the increase in p53-positive tubule cells after IR was greater in WT kidney than in mutant kidneys (9.9 Ϯ 1.4 cells/HPF versus 0.8 Ϯ 0.4 cells/HPF), which is consistent with the theory that DAPK activity stabilizes p53 protein. Finally, serum creatinine levels after IR were higher in WT mice than in mutant mice (2.54 Ϯ 0.34 mg/dl versus 0.87 Ϯ 0.24 mg/dl at 40 h after ischemia). Thus, these results indicate that deletion of the kinase domain from DAPK molecule can attenuate tubular cell apoptosis and renal dysfunction after IR injury.

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