title: Protein Inhibitor of NOS1 Plays a Central Role in the Regulation of NOS1 Activity in Human Dilated Hearts.
abstract: An essential factor for the production of nitric oxide by nitric oxide synthase 1 (NOS1), major modulator of cardiac function, is the cofactor tetrahydrobiopterin (BH4). BH4 is regulated by GTP cyclohydrolase 1, the rate-limiting enzyme in BH4 biosynthesis which catalyses the formation of dihydroneopterin 3'triphosfate from GTP, producing BH4 after two further steps catalyzed by 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase. However, there are other essential factors involved in the regulation of NOS1 activity, such as protein inhibitor of NOS1 (PIN), calmodulin, heat shock protein 90, and NOS interacting protein. All these molecules have never been analysed in human non-ischemic dilated hearts (DCM). In this study we demonstrated that the upregulation of cardiac NOS1 is not accompanied by increased NOS1 activity in DCM, partly due to the elevated PIN levels and not because of alterations in biopterin biosynthesis. Notably, the PIN concentration was significantly associated with impaired ventricular function, highlighting the importance of this NOS1 activity inhibitor in Ca(2+) homeostasis. These results take a central role in the current list of targets for future studies focused on the complex cardiac dysfunction processes through more efficient harnessing of NOS1 signalling.
authors.affiliation: Cardiocirculatory Unit, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Roselló-Lletí
authors.affiliation: Cardiocirculatory Unit, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Tarazón
authors.affiliation: Cardiocirculatory Unit, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Ortega
authors.affiliation: Cardiocirculatory Unit, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gil-Cayuela
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, United Kingdom.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Carnicer
authors.affiliation: Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, Santiago de Compostela, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Lago
authors.affiliation: Cellular and Molecular Cardiology Research Unit, Department of Cardiology and Institute of Biomedical Research, University Clinical Hospital, Santiago de Compostela, Spain.
authors.forename: Jose Ramón
authors.initials: JR
authors.lastname: González-Juanatey
authors.affiliation: Cardiocirculatory Unit, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Portolés
authors.affiliation: Cardiocirculatory Unit, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Rivera
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D056445:Cytoplasmic Dyneins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D001708:Biopterins; C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I; C427758:DYNLL1 protein, human; D056445:Cytoplasmic Dyneins; C003402:sapropterin