Abstract 12318: Midkine Deteriorates Atherosclerosis by its Proinflammatory, Angiogenic and Anti-Apoptotic Functions in Apolipoprotein-E Knockout Mice
Background: Midkine (MK) is a heparin-binding growth factor involved in diverse biological phenomena, e.g. neural survival, carcinogenesis, inflammation and tissue repair. We have demonstrated recently that MK plays a critical role in neointima formation in a rat carotid artery balloon injury model. However, the role of MK on atherosclerosis has not been investigated. In this study, we studied the effect of MK administration on atherogenesis in apolipoprotein E-knockout (ApoE-/-) mice.
Methods: Human recombinant MK protein was administrated for 12 weeks (12 μ g/day) by osmotic pump intraperitoneally in 8-week old C57BL/6 male ApoE-/- mice (ApoE-/- MK+, n=15) and ApoE+/+ mice (ApoE+/+ MK+, n=15) with a high-fat diet. Saline was administrated in the same manner for control group in ApoE-/- mice (ApoE-/- MK-, n=15) and ApoE+/+ mice (ApoE+/+ MK-, n=5).
Results: We analyzed mice atherosclerotic lesions in longitudinal sections from aortic root to common iliac artery by Sudan IV staining. Lesion area (Sudan IV positive area) was significantly increased by MK administration in ApoE-/- mice (ApoE-/- MK+: 26.3 ± 0.6%) compared for saline administration (ApoE-/- MK-: 6.8 ± 1.8%). On the contrary, there is no significant difference between ApoE+/+ MK- (1.5 ± 0.4%) and ApoE+/+ MK- (0.9 ± 0.7%). MK significantly increased mRNA levels of aorta in ApoE-/- mice in proinflammation and angiogenic factors (IL-1α, IL-1β, CCL2, IFN-γ, FgF and HgF). In the immunohistochemistry, macrophage of aortic roots lesions which was stained by Mac-3 was significantly increased in ApoE-/- MK+ compared with ApoE-/- MK- (35.9 ± 7.1% vs. 21.8 ± 6.3%). The percentage of TUNEL positive nuclei over total nuclei of the lesions of aortic roots were significantly decreased in ApoE-/- MK+ compared with ApoE-/- MK- (0.9 ± 0.7% vs. 2.6 ± 2.3%). There was no significant difference in serum LDL levels between ApoE-/- MK+ and ApoE-/- MK- (335.5 ± 60.2 vs. 299.0 ± 87.8 mg/dl), whereas they were significantly increased compared with ApoE+/+ mice; ApoE+/+ MK+ (12.5 ± 3.5 mg/dl) and ApoE+/+ MK- (10.8 ± 4.2 mg/dl).
Conclusions: MK deteriorates atherosclerosis by its proinflammatory, angiogenic and anti-apoptotic functions. Inhibition of MK could be a new therapeutic approach to prevent atherosclerosis.
- © 2011 by American Heart Association, Inc.