title: Genetic disruption of guanylyl cyclase/natriuretic peptide receptor-A upregulates ACE and AT1 receptor gene expression and signaling: role in cardiac hypertrophy.
abstract: Guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) signaling antagonizes the physiological effects mediated by the renin-angiotensin system (RAS). The objective of this study was to determine whether the targeted-disruption of Npr1 gene (coding for GC-A/NPRA) leads to the activation of cardiac RAS genes involved on the hypertrophic remodeling process. The Npr1 gene-knockout (Npr1(-/-)) mice showed 30-35 mmHg higher systolic blood pressure (SBP) and a 63% greater heart weight-to-body weight (HW/BW) ratio compared with wild-type (Npr1(+/+)) mice. The mRNA levels of both angiotensin-converting enzyme and angiotensin II type 1a receptor were increased by three- and fourfold, respectively, in Npr1(-/-) null mutant mice hearts compared with the wild-type Npr1(+/+) mice hearts. In parallel, the expression levels of interleukin-6 and tumor necrosis factor-alpha were increased by four- to fivefold, in Npr1(-/-) mice hearts compared with control animals. The NF-kappaB binding activity in nuclear extracts of Npr1(-/-) mice hearts was increased by fourfold compared with wild-type Npr1(+/+) mice hearts. Treatments with captopril or hydralazine equally attenuated SBP; however, only captopril significantly decreased the HW/BW ratio and suppressed cytokine gene expression in Npr1(-/-) mice hearts. The ventricular cGMP level was reduced by almost sixfold in Npr1(-/-) mice compared with wild-type control mice. The results of the present study indicate that disruption of NPRA/cGMP signaling leads to the augmented expression of cardiac RAS pathways that promote the development of cardiac hypertrophy and remodeling.
authors.affiliation: Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
authors.forename: Elangovan
authors.initials: E
authors.lastname: Vellaichamy
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
authors.forename: Naveen
authors.initials: N
authors.lastname: Somanna
authors.forename: Kailash N
authors.initials: KN
authors.lastname: Pandey
mesh_terms: D000804:Angiotensin II / Q000097:blood; D000818:Animals; D002216:Captopril / Q000494:pharmacology / Q000627:therapeutic use; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics*; D006152:Cyclic GMP / Q000502:physiology; D005355:Fibrosis; D005786:Gene Expression Regulation; D006162:Guanylate Cyclase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006352:Heart Ventricles / Q000473:pathology; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis* / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis* / Q000235:genetics; D017461:Receptors, Atrial Natriuretic Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D044140:Receptor, Angiotensin, Type 1; D017392:Thiobarbituric Acid Reactive Substances; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D006830:Hydralazine; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP