Copyright © 2004, European Society of Cardiology
Increased susceptibility to heart failure in response to volume overload in mice lacking natriuretic peptide receptor-A gene
aDepartment of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7525, United States
bDepartment of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan
* Corresponding author. Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. Tel.: +81 282 87 2149; fax: +81 282 86 1596. Email address: nishikim{at}dokkyomed.ac.jp
Object: 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 β-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.
Conclusion: These results provide genetic evidence that NPRA signaling protects against HF induced by volume overload in mice.
KEYWORDS Atrial natriuretic peptide; Natriuretic peptide receptor-A; Heart failure; Renin–aldosterone system; Natriuresis
Time for primary review 17 days
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