Increased susceptibility to heart failure in response to volume overload in mice lacking natriuretic peptide receptor-A gene.
OBJECTIVE
Contribution of the natriuretic peptide system to the development of heart failure (HF) in vivo was examined using mice lacking or having decreased natriuretic peptide receptor-A (NPRA), a guanylyl cyclase-linked receptor.


METHODS
Volume-overloaded HF was produced by aortocaval fistula in mice with wild-type (+/+), heterozygous (+/-), and homozygous null mutants (-/-) of the NPRA gene. Severity of HF was assessed 4 weeks after operation on the basis of organ weight, hemodynamics, echocardiographic indices, urinary variables, neurohumoral factors, and myocardial gene expression.


RESULTS
There were no significant differences in lung weight, kidney weight, left ventricular end-diastolic pressure (LVEDP), left ventricular systolic function, or urinary variables among the three sham-operated groups; however, sham-operated (-/-) mice had higher blood pressure and individual cardiac chamber weights than did (+/+) mice. In contrast, (-/-) mice with aortocaval fistula had higher LVEDP, left and right ventricular weights, lung weight, and left ventricular dimension, as well as lower fractional shortening and urinary sodium and cyclic guanosine monophosphate (cGMP) excretion than did (+/+) mice with aortocaval fistula. In addition, ventricular mRNA expression of natriuretic peptides and beta-myosin heavy chain increased markedly only in (-/-) mice. Plasma atrial natriuretic peptide, renin, and aldosterone, but not cGMP, showed greater responses to aortocaval fistula in (-/-) mice than in (+/+) mice. Both sham-operated and aortocaval fistula NPRA (+/-) mice almost consistently showed a phenotype intermediate between those of NPRA (-/-) and NPRA (+/+) mice.


CONCLUSIONS
These results provide genetic evidence that NPRA signaling protects against HF induced by volume overload in mice.
Nishikimi
Toshio
T
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7525, USA. nishikim@dokkyomed.ac.jp
Hagaman
John R
JR
Takahashi
Nobuyuki
N
Kim
Hyung-Suk
HS
Matsuoka
Hiroaki
H
Smithies
Oliver
O
Maeda
Nobuyo
N
D000450:Aldosterone / Q000097:blood; D000803:Angiotensin I / Q000097:blood; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000235:genetics; D001810:Blood Volume; D006152:Cyclic GMP / Q000097:blood / Q000652:urine; D004198:Disease Susceptibility; D006162:Guanylate Cyclase / Q000235:genetics* / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics* / Q000378:metabolism; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D020033:Protein Isoforms; D012333:RNA, Messenger; D020097:Natriuretic Peptide, Brain; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D000803:Angiotensin I; D012083:Renin; D018995:Myosin Heavy Chains; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP