Key result
Npr1 gene disruption in mice increases heart weight ratio by ~60% and elevates SBP.
Npr1 gene dose inversely correlates with cardiac proinflammatory mediators, hypertrophic markers, and NF-κB/AP-1-mediated mechanisms in mice.
Npr1 disruption models hypertensive cardiac hypertrophy in mice; hypothesis-generating for NPR1 modulation in human disease.
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.
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Vellaichamy et al. (2014) studied Cardiac inflammation and hypertrophy. Npr1 gene disruption (Npr1(-/-)) and gene duplication (Npr1(++/++)) vs. Wild-type (Npr1(+/+)) mice was evaluated on Cardiac expression of proinflammatory cytokines, hypertrophic markers, NF-κB, and AP-1. Npr1 gene disruption in mice increased systolic blood pressure by 41 mm Hg and heart weight to body weight ratio by 60% compared with wild-type mice.
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