title: The extracellular matrix metalloproteinase inducer EMMPRIN is a target of nitric oxide in myocardial ischemia/reperfusion.
abstract: Nitric oxide (NO) is an important defense against myocardial ischemia/reperfusion (I/R) injury. Although matrix metalloproteinase (MMP)-mediated necrosis of cardiac myocytes is well characterized, the role of inducible NO synthase (iNOS)-derived NO in this process is poorly understood. I/R injury was increased in iNOS-deficient mice and in mice treated with 1400 W (a pharmacological iNOS inhibitor) and was associated with significantly increased expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and EMMPRIN-associated MMPs. Transcriptional activity of an EMMPRIN luciferase promoter reporter expressed in cardiac myocytes was inhibited by NO in a cGMP-dependent manner, and this transcriptional inhibition was abolished by mutation of a putative E2F site. Consistent with these findings, EMMPRIN null mice, in which iNOS is normally induced, are partially protected against I/R injury. Pharmacological inhibition of iNOS in EMMPRIN null mice had no additional protective effect, suggesting that EMMPRIN is a downstream target of NO. Administration of anti-EMMPRIN neutralizing antibodies partly reduced the excess heart damage and MMP-9 expression induced by I/R in iNOS null mice, indicating that regulation of EMMPRIN is an important mechanism of NO-mediated cardioprotection.
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid 28029, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Tarin
authors.forename: Begoña
authors.initials: B
authors.lastname: Lavin
authors.forename: Monica
authors.initials: M
authors.lastname: Gomez
authors.forename: Marta
authors.initials: M
authors.lastname: Saura
authors.forename: Antonio
authors.initials: A
authors.lastname: Diez-Juan
authors.forename: Carlos
authors.initials: C
authors.lastname: Zaragoza
mesh_terms: D000818:Animals; D001483:Base Sequence; D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017931:DNA Primers; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D011401:Promoter Regions, Genetic
chemical_list: C497887:Bsg protein, mouse; D017931:DNA Primers; D051926:Basigin; D009569:Nitric Oxide