title: Nitric Oxide Induces Cardiac Protection by Preventing Extracellular Matrix Degradation through the Complex Caveolin-3/EMMPRIN in Cardiac Myocytes.
abstract: Inhibition of Extracellular Matrix degradation by nitric oxide (NO) induces cardiac protection against coronary ischemia/reperfusion (IR). Glycosylation of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) stimulates enzymatic activation of matrix metalloproteinases (MMPs) in the heart, although the mechanisms leading to EMMPRIN glycosylation are poorly understood. We sought to determine if NO may induce cardiac protection by preventing glycosylation of EMMPRIN in a mouse model of IR. Here we found that Caveolin-3 binds to low glycosylated EMMPRIN (LG-EMMPRIN) in cardiac cells and in the hearts of healthy mice, whereas IR disrupted the complex in nitric oxide synthase 2 (NOS2) knockout (KO) mice. By contrast, the binding was partially restored when mice were fed with an NO donor (DEA-NO) in the drinking water, showing a significant reduction on infarct size (NOS2KO: 34.6±5 vs NOS2KO+DEA-NO: 20.7±9), in expression of matrix metalloproteinases, and cardiac performance was improved (left ventricular ejection fraction (LVEF). NOS2KO: 31±4 vs NOS2KO+DEA-NO: 46±6). The role of Caveolin-3/EMMPRIN in NO-mediated cardiac protection was further assayed in Caveolin-3 KO mice, showing no significant improvement on infarct size (Caveolin-3 KO: 34.8±3 vs Caveolin-3 KO+DEA-NO:33.7±5), or in the expression of MMPs, suggesting that stabilization of the complex Caveolin-3/LG-EMMPRIN may play a significant role in the cardioprotective effect of NO against IR.
authors.affiliation: Department of Systems Biology (Physiology), University of Alcalá, School of Medicine (IRYCIS), Ctra. Madrid Barcelona, Km 3,300, 28875, Alcalá de Henares, Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Cuadrado
authors.affiliation: Cardiology Department, University Francisco de Vitoria/Hospital Ramón y Cajal Research Unit (IRYCIS), Ctra. Colmenar Viejo, km. 9100, 28034, Madrid, Spain.
authors.forename: Borja
authors.initials: B
authors.lastname: Castejon
authors.affiliation: Cardiology Department, University Francisco de Vitoria/Hospital Ramón y Cajal Research Unit (IRYCIS), Ctra. Colmenar Viejo, km. 9100, 28034, Madrid, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Martin
authors.affiliation: Department of Systems Biology (Physiology), University of Alcalá, School of Medicine (IRYCIS), Ctra. Madrid Barcelona, Km 3,300, 28875, Alcalá de Henares, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Saura
authors.affiliation: Department of Systems Biology (Physiology), University of Alcalá, School of Medicine (IRYCIS), Ctra. Madrid Barcelona, Km 3,300, 28875, Alcalá de Henares, Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Reventun-Torralba
authors.affiliation: Cardiology Department, University Hospital Ramón y Cajal (IRYCIS), Ctra Colmenar Viejo, km. 9100, 28034, Madrid, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Zamorano
authors.affiliation: Cardiology Department, University Francisco de Vitoria/Hospital Ramón y Cajal Research Unit (IRYCIS), Ctra. Colmenar Viejo, km. 9100, 28034, Madrid, Spain.
authors.forename: Carlos
authors.identifier: http://orcid.org/0000-0002-1706-8592
authors.initials: C
authors.lastname: Zaragoza
mesh_terms: D000818:Animals; D051926:Basigin / Q000378:metabolism*; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D006031:Glycosylation / Q000187:drug effects; D006834:Hydrazines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D046912:Multiprotein Complexes / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: C497887:Bsg protein, mouse; D051244:Caveolin 3; D006834:Hydrazines; D046912:Multiprotein Complexes; D020030:Nitric Oxide Donors; D020011:Protective Agents; D051926:Basigin; D009569:Nitric Oxide; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse