Many experimental and clinical studies have demonstrated that elevated leptin concentration in patients with obesity/metabolic
syndrome contributes to the pathogenesis of cardiovascular disorders including arterial hypertension, atherosclerosis, restenosis after
coronary angioplasty and myocardial hypertrophy. Receptor tyrosine kinases belonging to the ErbB family, especially ErbB1 (epidermal
growth factor receptor) and ErbB2 are abundantly expressed in the blood vessels and the heart. EGFR is activated not only by its multiple
peptide ligands but also by many other factors including angiotensin II, endothelin-1, norepinephrine, thrombin and prorenin; the phenomenon
referred to as “transactivation”. Augmented EGFR signaling contributes to abnormalities of vascular tone and renal sodium
handling as well as vascular remodeling and myocardial hypertrophy through various intracellular mechanisms, in particular extracellular
signal-regulated kinases (ERK) and phosphoinositide 3-kinase (PI3K). Recent experimental studies indicate that chronically elevated
leptin transactivates the EGFR through the mechanisms requiring reactive oxygen species and cytosolic tyrosine kinase, c-Src. In addition,
hyperleptinemia increases ErbB2 activity in the arterial wall. Stimulation of EGFR and ErbB2 downstream signaling pathways such
as ERK and PI3K in the vascular wall and the kidney may contribute to the increase in vascular tone, enhanced tubular sodium reabsorption
as well as vascular and renal lesions in hyperleptinemic obese subjects.
Keywords: Leptin, obesity, metabolic syndrome, atherosclerosis, restenosis, smooth muscle cells, epidermal growth factor receptor, ErbB
receptors, phosphoinositide 3-kinase.
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