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Genetic disruption of guanylyl cyclase/natriuretic peptide receptor-A upregulates ACE and AT1 receptor gene expression and signaling: role in cardiac hypertrophy

Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana

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- were increased by four- to fivefold, in Npr1^–/– mice hearts compared with control animals. The NF-B 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.

angiotensin-converting enzyme; angiotensin II type 1 receptor; hypertension; cardiac hypertrophy; angiotensin II; cytokines

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