title: Genetically altered mutant mouse models of guanylyl cyclase/natriuretic peptide receptor-A exhibit the cardiac expression of proinflammatory mediators in a gene-dose-dependent manner.
abstract: The objective of this study was to examine whether genetically determined differences in the guanylyl cyclase/natriuretic peptide receptor-A gene (Npr1) affect cardiac expression of proinflammatory cytokines, hypertrophic markers, nuclear factor-κB (NF-κB), and activating protein-1 (AP-1) in am Npr1 gene-dose-dependent manner. In the present studies, adult male Npr1 gene-disrupted (Npr1(-/-)), wild-type (Npr1(+/+)), and gene-duplicated (Npr1(++/++)) mice were used. The Npr1(-/-) mice showed 41 mm Hg higher systolic blood pressure and 60% greater heart weight to body weight (HW/BW) ratio; however, Npr1(++/++) mice exhibited 15 mm Hg lower systolic blood pressure and 12% reduced HW/BW ratio compared with Npr1(+/+) mice. Significant upregulation of gene expression of proinflammatory cytokines and hypertrophic markers along with enhanced NF-κB/AP-1 binding activities were observed in the Npr1(-/-) mouse hearts. Conversely, hypertrophic markers and proinflammatory cytokines gene expression as well as NF-κB/AP-1 binding activities were markedly decreased in Npr1(++/++) mouse hearts compared with wild-type mice. The ventricular guanylyl cyclase activity and cGMP levels were reduced by 96% and 87%, respectively, in Npr1(-/-) mice; however, these parameters were amplified by 2.8-fold and 3.8-fold, respectively, in Npr1(++/++) mice. Echocardiographic analysis revealed significantly increased fractional shortening in Npr1(++/++) mice (P < .05) but greatly decreased in Npr1(-/-) mice (P < .01) hearts compared with Npr1(+/+) mice. The present findings suggest that Npr1 represses the expression of cardiac proinflammatory mediators, hypertrophic markers, and NF-κB/AP-1-mediated mechanisms, which seem to be associated in an Npr1 gene-dose-dependent manner.
authors.affiliation: Department of Physiology Health Sciences Center (E.V., S.D., U.S., K.N.P.), Tulane University School of Medicine, New Orleans, Louisiana 70112; and Department of Pathology and Laboratory of Medicine (N.M.), University of North Carolina, Chapel Hill, North Carolina 27516.
authors.forename: Elangovan
authors.initials: E
authors.lastname: Vellaichamy
authors.forename: Subhankar
authors.initials: S
authors.lastname: Das
authors.forename: Umadevi
authors.initials: U
authors.lastname: Subramanian
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Maeda
authors.forename: Kailash N
authors.initials: KN
authors.lastname: Pandey
mesh_terms: D000818:Animals; D001835:Body Weight; D002467:Cell Nucleus / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005355:Fibrosis; D006162:Guanylate Cyclase / Q000378:metabolism; D006321:Heart / Q000502:physiology; D006352:Heart Ventricles / Q000378:metabolism; D006984:Hypertrophy; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009929:Organ Size; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics* / Q000378:metabolism*; D013599:Systole; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP