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Inhibition of matrix metalloproteinase (MMP)‐dependent epidermal growth factor receptor (EGFR) transactivation prevents the development of hypertension in high fructose diet fed rats
Author(s) -
Nagareddy Prabhakara Reddy,
Vasudevan Harish,
McClure Brian,
McNeill John H.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.912.37
Subject(s) - transactivation , endocrinology , medicine , fructose , endothelial dysfunction , endothelin receptor , insulin resistance , metabolic syndrome , epidermal growth factor receptor , matrix metalloproteinase , receptor , pharmacology , diabetes mellitus , biology , biochemistry , transcription factor , gene
The metabolic syndrome is a cluster of cardiovascular risk factors among which are insulin resistance (IR) and hypertension. Despite major research efforts, it remains uncertain what causes the hypertension. Recent studies have suggested a link between disease progression and activation of growth factor receptor signaling pathways. A key event in this pathway is transactivation of growth factor receptors, such as the EGFR by MMPs. This transactivation can be triggered by agonists such as catecholamines, endothelin‐I and angiotensin II, all of which are elevated in models of hypertension including high fructose diet fed rats. We hypothesize that the increased activity of MMPs (MMP‐7) and subsequent transactivation of the EGFR contributes to the development of hypertension in high fructose diet fed rats. Male Wistar rats were fed with either normal rat chow or a 60% fructose diet for 10 weeks and treated daily with doxycycline (MMP inhibitor, 20 mg/kg) and AG 1478 (EGFR inhibitor, 5 mg/kg) orally for 4 weeks. Fructose fed rats developed IR, endothelial dysfunction and hypertension. Western and substrate zymographic analysis indicated increased expression and activity of MMP‐7 in cardiovascular tissues of untreated fructose rats. Inhibition of either MMP or the EGFR activity prevented endothelial dysfunction and development of hypertension without affecting IR. Our results suggest that the MMP‐EGFR pathway may be a potential target for the treatment of hypertension in metabolic syndrome. Funded by HSFC, CIHR & MSFHR.