Regulation of cardiac angiotensin‐converting enzyme and angiotensin AT1 receptor gene expression in Npr1 gene‐disrupted mice

1. Understanding of the regulatory mechanisms of gene expression in the control of blood pressure and fluid volume is a key issue in cardiovascular medicine. Guanylyl cyclase/natriuretic peptide receptor‐A (GC‐A/NPRA) signalling antagonizes the physiological and pathophysiological effects mediated by the renin–angiotensin–aldosterone system (RAAS) in the regulation of cardiovascular homeostasis. 2. The targeted‐disruption of the Npr1 gene (coding for GC‐A/PRA) leads to activation of the cardiac RAAS involved in the hypertrophic remodelling process, which influences cardiac size, expression of pro‐inflammatory cytokine genes and the behaviour of various hypertrophy marker genes. The Npr1 gene‐knockout (Npr1^?/?) mice exhibit 35–40 mmHg higher systolic blood pressure and a significantly greater heart weight to bodyweight ratio than wild‐type (Npr1^+/+) mice. 3. The expression of both angiotensin‐converting enzyme (ACE) and angiotensin II AT_1a receptors are significantly increased in hearts from Npr1^?/? mice compared with hearts from Npr1^+/+ mice. In parallel, the expression of interleukin‐6 and tumour necrosis factor‐α is also markedly increased in hearts from Npr1^?/? mice. 4. These findings indicate that disruption of NPRA/cGMP signalling leads to augmented expression of the cardiac RAAS in conjunction with pro‐inflammatory cytokines in Npr1‐null mutant mice, which promotes the development of cardiac hypertrophy and remodelling.