GENETIC DISRUPTION OF NPR1 UPREGULATES CARDIAC EXPRESSION OF PROINFLAMMATORY MEDIATORS


Kailash N. Pandey, Ph.D. Tulane University School of Medicine, New Orleans, LA, USA

Proinflammatory cytokines play a central role in the pathophysiology and development of endothelial dysfunction, cardiac hypertrophy, and heart failure in experimental animal models and humans. We have examined whether genetically determined differences in guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene (Npr1) affect cardiac expression of proinflammatory cytokines, hypertrophic markers, and nuclear factor kappa-B (NF-kB) in a Npr1 gene-dose-dependent manner. Gene-disrupted Npr1-/- mice showed 41 mmHg higher systolic blood pressure (SBP) and 60% greater heart weight/body weight (HW/BW) ratio compared with Npr1+/+ wild-type mice. Significant up-regulation of proinflammatory cytokines and hypertrophic markers gene expression along with enhanced NF-kB binding activities were observed in Npr1 gene-disrupted mice hearts. On the other hand, the expression of hypertrophic markers and proinflammatory cytokine genes along with NF-kB binding activities were markedly decreased in Npr1 gene-duplicated (Npr1++/++) mice hearts. The guanylyl cyclase activity and intracellular cGMP levels in ventricular tissues were reduced by 97% and 90%, respectively, in Npr1 gene-disrupted mice, but these parameters were increased by 3.0-fold and 3.8-fold, respectively, in Npr1 gene-duplicated mice hearts compared with wild-type mice hearts. M-mode echocardiographic analysis indicated that the fractional shorting was greatly reduced in Npr1 gene-disrupted mice, while significantly enhanced in Npr1 gene-duplicated mice compared with wild-type mice hearts. It is implicated that the Npr1 gene represses the expression of cardiac proinflammatory mediators, hypertrophic markers, and NF-kB-mediated mechanisms to enhance the cardiac function and protection of heart in the disease states.