INHIBITION OF NUCLEAR FACTOR κB INDUCES REGRESSION OF CARDIAC HYPERTROPHY IN MICE LACKING NATRIURETIC PEPTIDE RECEPTOR A.

Abstract

Guanylyl cyclase A/natriuretic peptide receptor A (GC-A/NPRA) is the principal receptor for the cardiac hormones atrial and brain natriuretic peptides (ANP and BNP). Mice carrying targeted disruption of Npr1 gene (encoding for GC-A/NPRA) exhibit hypertension, marked cardiac hypertrophy, and congestive heart failure with sudden death. The objective of the present study was to determine whether disruption of NPRA activates the nuclear factor κB (NF-κB) and further to evaluate whether the inhibition of NF-κB signaling can attenuate cardiac hypertrophy in mice lacking NPRA. We analyzed hypertrophy marker genes expression, NF-κB nuclear translocation, IKK-kinase activity, and IκB-α phosphorylation status in the ventricular tissues of 16-week-old male Npr1 gene-disrupted (Npr1−/−) and wild-type (Npr1+/+) mice. Electrophoretic mobility shift assay (EMSA) was performed with NF-[203}B-specific oligonucleotides in the nuclear extracts isolated from the ventricular tissues of Npr1−/−and Npr1+/+mice. NF-κB subunits (p65 and p50) protein levels and IκB-α phosphorylation status were analyzed using specific antibodies. Heart weight/body weight ratio and hypertrophy marker genes c-fos (p