Transactivation of ErbB Receptors by Leptin in the Cardiovascular System: Mechanisms, Consequences and Target for Therapy

Author(s): Jerzy Beltowski, Anna Jazmroz-Wisniewska.

Journal Name: Current Pharmaceutical Design

Volume 20 , Issue 4 , 2014

Abstract:

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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Article Details

VOLUME: 20
ISSUE: 4
Year: 2014
Page: [616 - 624]
Pages: 9
DOI: 10.2174/138161282004140213155050
Price: $65

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