Targeted disruption of the gene for natriuretic peptide receptor-A worsens hypoxia-induced cardiac hypertrophy.
Targeted disruption of the gene for natriuretic peptide receptor-A (NPR-A) worsens pulmonary hypertension and right ventricular hypertrophy during hypoxia, but its effect on left ventricular mass and systemic pressures is not known. We examined the effect of 3 wk of hypobaric hypoxia (0.5 atm) on right and left ventricular pressure and mass in mice with 2 (wild type), 1, or 0 copies of Npr1, the gene that encodes for NPR-A in mice. Under normoxic conditions, right ventricular peak pressure (RVPP) was greater in 0 than in 2 copy mice, but there were no genotype-related differences in carotid artery PP (CAPP). The left ventricular free wall weight-to-body weight (LV/body wt) ratio was greater in 0 than in 2 copy mice and there was a trend toward a greater right ventricular weight-to-body weight (RV/body wt) ratio. Three weeks of hypoxia increased RVPP and RV/body wt in all genotypes. The increase in RVPP was similar in all genotypes (11-14 mmHg), but the hypoxia-induced increase in RV/body wt was more than twice as great in 0 copy mice than in 2 copy mice (1.11 +/- 0.06 to 2.65 +/- 0.46 vs. 0.96 +/- 0.04 to 1.4 +/- 0.09, P < 0.05). Chronic hypoxia had no effect on CAPP in any genotype and did not effect LV/body wt in 1 or 2 copy mice, but increased LV/body wt 41% in 0 copy mice. We conclude that absent expression of NPR-A worsens right ventricular hypertrophy and causes left ventricular hypertrophy during exposure to chronic hypoxia without increasing pulmonary or systemic arterial pressure responses.
Klinger
James R
JR
Division of Pulmonary, Sleep, and Critical Care Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, RI 02903, USA. James_Klinger@brown.edu
Warburton
Rod R
RR
Pietras
Linda
L
Oliver
Paula
P
Fox
Jennifer
J
Smithies
Oliver
O
Hill
Nicholas S
NS
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D006332:Cardiomegaly / Q000209:etiology / Q000503:physiopathology*; D002339:Carotid Arteries / Q000503:physiopathology; D018450:Disease Progression; D006162:Guanylate Cyclase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006909:Hydroxyproline / Q000032:analysis; D000860:Hypoxia / Q000150:complications / Q000503:physiopathology*; D008168:Lung / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011652:Pulmonary Circulation / Q000502:physiology; D017461:Receptors, Atrial Natriuretic Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013599:Systole; D016277:Ventricular Function, Left / Q000502:physiology; D016278:Ventricular Function, Right / Q000502:physiology
D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006909:Hydroxyproline