Right ventricular nitric oxide signaling in an ovine model of congenital heart disease: a preserved fetal phenotype.
We recently reported superior right ventricle (RV) performance in response to acute afterload challenge in lambs with a model of congenital heart disease with chronic left-to-right cardiac shunts. Compared with control animals, shunt lambs demonstrated increased contractility because of an enhanced Anrep effect (the slow increase in contractility following myocyte stretch). This advantageous physiological response may reflect preservation of a fetal phenotype, since the RV of shunt lambs remains exposed to increased pressure postnatally. Nitric oxide (NO) production by NO synthase (NOS) is activated by myocyte stretch and is a necessary intermediary of the Anrep response. The purpose of this study was to test the hypothesis that NO signaling is increased in the RV of fetal lambs compared with controls and shunt lambs have persistence of this fetal pattern. An 8-mm graft was placed between the pulmonary artery and aorta in fetal lambs (shunt). NOS isoform expression, activity, and association with activating cofactors were determined in fetal tissue obtained during late-gestation and in 4-wk-old juvenile shunt and control lambs. We demonstrated increased RNA and protein expression of NOS isoforms and increased total NOS activity in the RV of both shunt and fetal lambs compared with control. We also found increased NOS activation and association with cofactors in shunt and fetal RV compared with control. These data demonstrate preserved fetal NOS phenotype and NO signaling in shunt RV, which may partially explain the mechanism underlying the adaptive response to increased afterload seen in the RV of shunt lambs.
Department of Pediatrics, University of California, San Francisco, San Francisco, California; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California;
Rebecca Johnson
RJ
Kameny
Department of Surgery, University of California, San Francisco, San Francisco, California; and.
Youping
Y
He
Department of Pediatrics, University of California, San Francisco, San Francisco, California;
Catherine
C
Morris
Department of Pediatrics, University of California, San Francisco, San Francisco, California;
Christine
C
Sun
Department of Pediatrics, University of California, San Francisco, San Francisco, California;
Michael
M
Johengen
Department of Pediatrics, University of California, San Francisco, San Francisco, California;
Wenhui
W
Gong
Department of Surgery, University of California, Davis, Davis, California.
Gary W
GW
Raff
Department of Pediatrics, University of California, San Francisco, San Francisco, California;
Sanjeev A
SA
Datar
Department of Pediatrics, University of California, San Francisco, San Francisco, California; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California;
Peter E
PE
Oishi
Department of Pediatrics, University of California, San Francisco, San Francisco, California; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California; jeff.fineman@ucsf.edu.
Jeffrey R
JR
Fineman
D000818:Animals; D001011:Aorta / Q000601:surgery; D004195:Disease Models, Animal; D005333:Fetus / Q000378:metabolism*; D006330:Heart Defects, Congenital / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D006352:Heart Ventricles / Q000201:enzymology / Q000378:metabolism*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000503:physiopathology; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011651:Pulmonary Artery / Q000601:surgery; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012756:Sheep; D015398:Signal Transduction
D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase
Anrep effect; right ventricle