We hypothesized that a single copy of the proatrial
natriuretic peptide gene (
Nppa+/-) would not be adequate to protect heterozygous mice against exaggerated
cardiac hypertrophy and remodeling after pressure-overload stress.
Nppa+/+,
Nppa+/-, and
Nppa-/- mice were subjected to
sham surgery or transverse aortic constriction and fed a basal
salt diet. Heart weight varied inversely with
Nppa gene load by 1 week after either surgery. Fractional shortening did not differ among genotypes at baseline and fell in
Nppa-/- mice only after transverse aortic constriction. There was a graded response in
collagen deposition related to
atrial natriuretic peptide (
ANP) expression after either surgery. A robust interstitial and perivascular
fibrosis was noted in
Nppa-/- and
Nppa+/- but not in
Nppa+/+ mice after transverse aortic constriction. Our findings are consistent with a growing body of evidence that
ANP is an important modulator of
cardiac hypertrophy and remodeling in response to hemodynamic stress. The observation that partial
ANP deficiency results in exaggerated
hypertrophy and remodeling after pressure overload suggests that genetic or environmental variation in
ANP levels may play a role in the development of
cardiac hypertrophy, remodeling, and failure in humans.