title: Enhanced activation of pro-inflammatory cytokines in mice lacking natriuretic peptide receptor-A.
abstract: Natriuretic peptide receptor-A (NPRA) is the principal receptor for the cardiac hormones ANP and BNP. Mice lacking NPRA develop progressive cardiac hypertrophy and congestive heart failure. However, the mechanisms responsible for hypertrophic growth in the absence of NPRA signaling are not yet known. In the present study, we determined whether deficiency of NPRA/cGMP signaling alters the cardiac pro-inflammatory cytokines gene expression in Npr1 (coding for NPRA) gene-knockout (Npr1(-/-)) mice exhibiting cardiac hypertrophy and fibrosis as compared with control wild-type (Npr1(+/+)) mice. A significant up-regulation of cytokine genes such as TNF-alpha (five-fold), IL-6 (three-fold) and TGF-beta1 (four-fold) were observed in mutant mice hearts lacking NPRA as compared with the age-matched wild-type mice. In parallel, NF-kappaB binding activity was almost five-fold greater in the nuclear extract of Npr1(-/-) mutant mice hearts as compared with wild-type Npr1(+/+) mice hearts. Guanylyl cyclase (GC) activity and cGMP levels were drastically reduced by 10- and 5-fold, respectively, in ventricular tissues of mutant mice hearts relative to wild-type controls. The present findings provide direct evidence that ablation of NPRA/cGMP signaling activates inflammatory cytokines, probably via NF-kappaB mediated signaling pathway, and is associated with hypertrophic growth of null mutant mice hearts.
authors.affiliation: Department of Physiology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Elangovan
authors.initials: E
authors.lastname: Vellaichamy
authors.forename: Kiran
authors.initials: K
authors.lastname: Kaur
authors.forename: Kailash N
authors.initials: KN
authors.lastname: Pandey
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D006152:Cyclic GMP / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009841:Oligonucleotides / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D016328:NF-kappa B; D009841:Oligonucleotides; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP