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.


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.
Department of Cardiology and Pneumology, University Hospital Benjamin Franklin, Free University of Berlin, Hindenburgdamm 30, D-12200, Berlin, Germany. thomas.walther@ukbf.fu-berlin.de
Thomas
T
Walther
Katrin
K
Klostermann
Silvia
S
Heringer-Walther
Heinz-Peter
HP
Schultheiss
Carsten
C
Tschöpe
Holger
H
Stepan
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D005355:Fibrosis / Q000235:genetics* / Q000503:physiopathology*; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011945:Receptors, Angiotensin / Q000172:deficiency / Q000235:genetics
D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D020097:Natriuretic Peptide, Brain