ROLE OF EPIDERMAL GROWTH FACTOR RECEPTOR IN THE PATHOGENESIS AND TREATMENT OF ARTERIAL HYPERTENSION
Jerzy Beltowski and Anna Jamroz-Wisniewska
Department of Pathophysiology, Medical University, Lublin, Poland
Epidermal growth factor receptor (EGFR) is a member of receptor tyrosine kinase family. Upon ligand binding, EGFR undergoes autophosphorylation at several tyrosine residues within its intracellular domain and triggers a number of signaling pathways including extracellular signal-regulated kinases, phospholipase C?, and phosphoinositide 3-kinase. EGFR regulates cell growth, proliferation and survival, and its overexpression or oncogenic mutations are observed in many human cancers. Therefore, several drugs have been developed to target EGFR for antitumor therapy. In the cardiovascular system, enhanced EGFR signaling is involved in vascular and myocardial hypertrophy. Recent studies suggest that EGFR may contribute to the development of arterial hypertension. Stimulated EGFR induces vasoconstriction and regulates renal tubular Na+ transport. Apart from its cognate ligand, EGFR is activated by many vasoconstrictors including angiotensin II, norepinephrine and endothelin-1. Enhanced EGFR signaling has been observed in several animal models of hypertension, and synthetic EGFR inhibitors reduce blood pressure in some of these models. Leptin, a peptide hormone which is produced by white adipose tissue and circulates in increased amounts in obese subjects, transactivates EGFR in vascular wall and the kidney, and EGFR inhibitor, AG1478, reduces blood pressure in experimental hyperleptinemia, suggesting that leptin-induced activation of EGFR may be involved in the pathogenesis of hypertension associated with the metabolic syndrome. These data suggest that inhibiting EGFR could be a novel therapeutic strategy for the treatment of hypertension. In addition, some of currently used hypotensive medications, in particular inhibitors of the renin-angiotensin-aldosterone system, modulate EGFR signaling.
Biomed Rev 2007; 18: 1-26.
Key words: ErbB receptors, receptor transactivation, extracellular signal-regulated kinases, receptor tyrosine kinase inhibitors, leptin, metabolic syndrome
Received 5 November 2007, accepted 4 December 2007.
Correspondence and reprint request to Dr Jerzy Bełtowski, Department of Pathophysiology, Medical University, ul. Jaczewskiego
8, PL-20-090 Lublin, Poland. Tel.: 48 81 7425 837, Fax: 48 81 7425 828,