Right ventricular hypertrophy with early dysfunction: A proteomics study in a neonatal model.
OBJECTIVE
Right ventricular hypertrophy and subsequent dysfunction is common in patients with congenital heart defects, but the molecular mechanisms underlying change from adaptive hypertrophy to dysfunction remain elusive. We used the novel technique of proteomics to characterize protein changes in right ventricular myocardium in a neonatal model of right ventricular hypertrophy and early dysfunction.


METHODS
Twelve neonatal piglets were equally randomized to pulmonary artery banding (PAB group), or sham operation (thoracotomy without banding). After 4 weeks, right ventricular morphology and function were assessed in vivo using magnetic resonance imaging. Animals were humanely killed. Proteomics of right ventricular myocardium was performed. Purified right ventricular proteins were separated by 2-dimensional difference gel electrophoresis using fluorescent cyanine dyes. After gel imaging, software analysis revealed protein spots differentially expressed between the 2 groups; these spots were excised and identified by mass spectrometry.


RESULTS
On magnetic resonance imaging, animals with pulmonary artery banding demonstrated significant right ventricular hypertrophy, cavity dilatation, and mild systolic impairment (right ventricular ejection fraction 39.8% +/- 15% vs 56.7% +/- 10% controls; P < .05). Right ventricular free wall mass on harvest confirmed right ventricular hypertrophy. Proteomic analysis revealed 18 proteins that were significantly differentially expressed: 5 structural proteins, 6 metabolic enzymes, 2 stress proteins, and 5 miscellaneous proteins. Expression of calsarcin-1 and vinculin was increased, as were certain metabolic enzymes, although F(1)-ATPase beta-chain and heat shock protein 70 decreased.


CONCLUSIONS
This is the first study characterizing right ventricular protein changes in a large animal model specifically capturing the change from compensated to maladaptive hypertrophy. These findings can guide future work at elucidating the mechanisms in the pathophysiology of neonatal right ventricular hypertrophy and dysfunction.
Sheikh
Amir M
AM
Department of Pediatric Cardiac Surgery, the Neuroproteomics Center, Durham, NC, USA. amsheikh10@hotmail.com
Barrett
Cindy
C
Villamizar
Nestor
N
Alzate
Oscar
O
Valente
Anne Marie
AM
Herlong
J Rene'
JR
Craig
Damian
D
Lodge
Andrew
A
Lawson
Jeffrey
J
Milano
Carmelo
C
Jaggers
James
J
D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D005786:Gene Expression Regulation; D006334:Heart Function Tests; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D017380:Hypertrophy, Right Ventricular / Q000235:genetics* / Q000473:pathology; D008026:Ligation; D008279:Magnetic Resonance Imaging; D011336:Probability; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D011651:Pulmonary Artery / Q000601:surgery; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D013318:Stroke Volume; D013552:Swine; D013997:Time Factors; D020858:Tissue and Organ Harvesting; D018497:Ventricular Dysfunction, Right / Q000235:genetics* / Q000473:pathology
D006360:Heat-Shock Proteins; D011506:Proteins