title: EMMPRIN mediates beta-adrenergic receptor-stimulated matrix metalloproteinase activity in cardiac myocytes.
abstract: Extracellular matrix metalloproteinase inducer (EMMPRIN) expression is increased in myocardium from patients with dilated cardiomyopathy and animal models of heart failure. However, little is known about the regulated expression or functional role of EMMPRIN in the myocardium. In rat cardiac cells, EMMPRIN is expressed on myocytes but not endothelial cells or fibroblasts. Therefore, we tested the hypothesis that EMMPRIN expression regulates matrix metalloproteinase (MMP) activity in rat ventricular myocytes in vitro. In adult rat ventricular myocytes (ARVM), beta-adrenergic receptor (betaAR) stimulation and H(2)O(2) (24 h) each increased EMMPRIN expression as assessed by immunoblotting. Pretreatment with a catalase/superoxide dismutase mimetic or adenoviral-mediated expression of catalase or a dominant-negative c-jun N-terminal kinase-1 (JNK) mutant inhibited the betaAR- and H(2)O(2)-stimulated increases in EMMPRIN expression suggesting that EMMPRIN expression is regulated via a reactive oxygen species-dependent JNK pathway. To determine whether EMMPRIN expression regulates matrix metalloproteinase (MMP) activity, EMMPRIN activity was inhibited by adenoviral expression of an inhibitory mutant of EMMPRIN. Expression of mutant EMMPRIN inhibited the betaAR-stimulated increases in MMP2 expression and zymographic MMP activity. Thus, in cardiac myocytes betaAR stimulation induces the expression of EMMPRIN via the ROS-dependent activation of JNK. The resulting increase in EMMPRIN activity stimulates MMP expression and activity. These findings suggest that in the myocardium the regulated expression of EMMPRIN is a determinant of MMP activity and may thus play a role in myocardial remodeling.
authors.affiliation: Myocardial Biology Unit, Boston University School of Medicine, 650 Albany Street, X740, Boston, MA 02118, USA. dasiwik@bu.edu
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Siwik
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Kuster
authors.forename: Jamin V
authors.initials: JV
authors.lastname: Brahmbhatt
authors.forename: Zaheer
authors.initials: Z
authors.lastname: Zaidi
authors.forename: Julia
authors.initials: J
authors.lastname: Malik
authors.forename: Henry
authors.initials: H
authors.lastname: Ooi
authors.forename: Ghassan
authors.initials: G
authors.lastname: Ghorayeb
mesh_terms: D000818:Animals; D051926:Basigin / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005799:Genes, Dominant; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
chemical_list: C497886:BSG protein, human; D001798:Blood Proteins; C079432:Bsg protein, rat; D017382:Reactive Oxygen Species; D011943:Receptors, Adrenergic, beta; D051926:Basigin; D006861:Hydrogen Peroxide; D002374:Catalase; D048031:JNK Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases