Studies performed during the last decade indicate that adipose tissue is not only a site of triglyceride storage but also an active endocrine organ which secretes many biologically active mediators referred to as "adipokines". In contrast to many adipokines which are overproduced in obese individuals and exert deleterious effects on insulin sensitivity, lipoprotein metabolism and cardiovascular system, such as leptin, tumor necrosis factor-alpha, plasminogen activator inhibitor-1, resistin, etc., adiponectin seems to be a unique adipokine which is produced in lower amounts in obese than in lean subjects and possesses predominantly beneficial activities, i.e. increases insulin sensitivity, stimulates fatty acid oxidation, inhibits inflammatory reaction and induces endothelium-dependent nitric oxide-mediated vasorelaxation. Adiponectin binds two receptors, AdipoR1 and AdipoR2. Adiponectin knockout mice exhibit various manifestations of the metabolic syndrome such as insulin resistance, glucose intolerance, hyperlipidemia, impaired endothelium-dependent vasorelaxation and hypertension, as well as augmented neointima formation after vascular injury. Clinical studies indicate that plasma adiponectin concentration is lower in patients with essential hypertension and ischemic heart disease. Raising endogenous adiponectin level or increasing the sensitivity to this hormone may be a promising therapeutic strategy for patients with metabolic and cardiovascular diseases. Among currently used drugs, thiazolidinediones (peroxisome proliferator activated receptor gamma agonists) are most effective in elevating adiponectin level.

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Phosphoinositide 3-kinase (PI3K) phosphorylates phosphatidylinositol 4,5-diphosphate to phosphatidylinositol 3,4,5-triphosphate which then activates multiple intracellular signaling proteins such as protein kinase B (Akt), glycogen synthase kinase-3β, mammalian target of rapamycin (mTOR), etc. PI3K is involved in the regulation of vascular smooth muscle cell contractility, migration and proliferation-processes crucial for the pathogenesis of hypertension, atherosclerosis and restenosis. Increased leptin concentration in the metabolic syndrome contributes to the pathogenesis of cardiovascular diseases, but the effect of leptin on vascular smooth muscle cells is controversial. We examined the effect of experimentally induced hyperleptinemia on PI3K activity in the rat aortic media in adult male Wistar rats. Leptin, administered for 10 days in increasing dose (from 0.05 to 0.25 mg/kg every 12 hours), increased PI3K activity in the aortic media about 5-fold. The effect of leptin was markedly attenuated by epidermal growth factor receptor (EGFR) inhibitor, AG1478, as well as by the ErbB2 receptor inhibitor, AG825. In addition, leptin increased tyrosine phosphorylation of ErbB2, which was abolished by either AG1478 or AG825. These results indicate that hyperleptinemia increases the activity of vascular ErbB2 receptor in EGFR-dependent manner. In addition, both EGFR and ErbB2 contribute to PI3K stimulation by leptin. Activation of ErbB2 and PI3K may contribute to detrimental effects of leptin on vascular contractility and remodeling and may be involved, at least in part, in the relationship between metabolic syndrome and increased risk of vascular restenosis after angioplasty.