Leptin stimulates phosphoinositide 3-kinase in the vascular wall: role of ErbB receptors

Abstract

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.

Obesity and kidney disease: Beyond the hyperfiltration

“…The binding of different Erb-B ligands and the combination of Erb-B homo- and heterodimer receptors can activate distinct downstream pathways, including the mitogen activated protein kinase (MAPK) and the phosphatidylinosithol-3kinase (PI3K) signaling pathways (35), which are able to control cellular behavior by transducing cell signals to the nucleus, then influencing the activity of transcription factors. Based on these assumptions, Beltowski et al have demonstrated the ability of high levels of leptin to transactivate the EGF receptor and activate the receptor Erb-B2 (40). Increased PI3K activity has been observed in the aortic media of adult male Wistar rats exposed to increasing doses of leptin for 10 days, which was markedly attenuated by the EGFR inhibitor AG1478 and by the ErbB2 receptor inhibitor AG825.…”