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

摘要

The objective of this study was to examine whether genetically determined differences in the guanylyl cyclaseatriuretic 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.