In addition to its insulin-sensitizing effect, adiponectin possesses direct antiatherogenic properties (30,31). Both adenovirus-mediated overexpression of full-length adiponectin (32) and transgenic overexpression of globular adiponectin (20) have been shown to inhibit atherosclerotic lesion formation in the aortic sinus of apoE-deficient mice. On the other hand, disruption of the adiponectin gene results in impaired vaso-reactivity (33) and increased neointimal thickening in response to external vascular cuff injury (23,34).
Adiponectin can act directly on the vascular system to exert its vasoprotective functions. In endothelial cells, full-length adiponectin enhances eNOS activity and increases nitric oxide (NO) production, which in turn improves endothelium-dependent vasodilation (35). This protein also suppresses TNF-a-induced production of proinflammatory chemokines and adhesion molecules, including interleukin-8 (36), intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, and E-selectin (37). Globular adiponectin has been shown to inhibit cell proliferation and suppress superoxide release induced by oxidized LDL in bovine aortic endothelial cells (38). In addition, the HMW form of adiponectin can protect endothelial cells from apoptosis by activation of AMPK (14).
In cultured aortic smooth muscle cells, adiponectin inhibits cell proliferation and migration induced by several atherogenic growth factors, including heparin-binding epidermal growth factor-like growth factor, platelet-derived growth factor BB, and basic fibroblast growth factor (12,39). Adiponectin oligomers interact with these growth factors and subsequently block their binding to the respective cell membrane receptors. In macrophages, adiponectin prevents lipid accumulation and suppresses foam cell transformation by inhibiting expression of the class A scavenger receptors and uptake of acety-lated low density lipoprotein particles (40). It also blocks the attachment of monocytes to endothelial cells, which is the first and crucial step of atherosclerosis (41). A more recent study has shown that adiponectin increases tissue inhibitor of metalloproteinase-1 through inducing interleukin-10 expression in primary human macrophages (42).
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