Fibrosis rather than blood pressure determines cardiac BNP expression in mice.

Background: Since first reports demonstrated interactions between the natriuretic peptide (NPS) and renin-angiotensin system (RAS), our experiments should clarify whether cardiac brain natriuretic peptide (BNP) is regulated in mice genetically altered for components of the RAS.

Methods And Results: The study was carried out in hypotensive AT1- and angiotensinogen (ANG)-, and normotensive AT2-knockout mice, and in hypertensive animals overexpressing ANG and wildtype controls of each genotype. Ventricular BNP expression was analyzed by RNase-protection assay (RPA) (n=6). Cardiac fibrosis was visualized by Sirius red staining. While ANG overexpression increases cardiac BNP-mRNA expression (1035+/-210 vs. wildtype: 405+/-95 in PSL/mm(2), P<0.01), its deficiency had no influence. Both AT1- and AT2-knockouts showed significantly decreased BNP-mRNA concentrations (AT1: 21+/-6 vs. wildtype: 139+/-28 in PSL/mm(2), P<0.001; AT2: 8+/-2 vs. 19+/-3 in PSL/mm(2), P<0.05). These alterations correlate to reduced cardiac fibrosis in AT2-deficient animals, and an unchanged matrix content in ANG knockouts.

Conclusions: Increased BNP-mRNA levels in hypertensive ANG-overexpressing mice and decreased BNP in hypotensive AT1-deficient animals suggest that this mRNA expression is blood pressure-dependent. However, the observed alterations of fibrosis and the unchanged BNP in hypotensive ANG knockouts and impaired BNP-mRNA expression in normotensive AT2-deficient mice demonstrate a direct interaction of the RAS and NPS that is fibrosis- rather than blood pressure-dependent.