Dynamic changes of gene expression in hypoxia-induced right ventricular hypertrophy.
Hypobaric hypoxia induces right ventricular hypertrophy. The relative contribution of pulmonary hypertension, decreased arterial oxygen, and neuroendocrine stimulation to the transcriptional profile of hypoxia-induced right ventricular hypertrophy is unknown. Whereas both ventricles are exposed to hypoxia and neuroendocrine stimulation, only the right ventricle is exposed to increased load. We postulated that right ventricular hypertrophy would reactivate the fetal gene transcriptional profile in response to increased load. We measured the expression of candidate genes in the right ventricle of rats exposed to hypobaric hypoxia (11% O(2)) and compared the results with the left ventricle. Hypoxia induced right ventricular hypertrophy without fibrosis. In the right ventricle only, atrial natriuretic factor transcript levels progressively increased starting at day 7. Metabolic genes were differentially regulated, suggesting a substrate switch from fatty acids to glucose during early hypoxia and a switch back to fatty acids by day 14. There was also a switch in myosin isogene expression and a downregulation of sarcoplasmic/endoplasmic ATPase 2a during early hypoxia, whereas later, both myosin isoforms and SERCA2a were upregulated. When the right and left ventricle were compared, the transcript levels of all genes, except for myosin isoforms and pyruvate dehydrogenase kinase-4, differed dramatically suggesting that all these genes are regulated by load. Our findings demonstrate that hypoxia-induced right ventricular hypertrophy transiently reactivates the fetal gene program. Furthermore, myosin iso-gene and pyruvate dehydrogenase kinase-4 expression is not affected by load, suggesting that either hypoxia itself or neuroendocrine stimulation is the primary regulator of these genes.
Sharma
Saumya
S
Dept. of Internal Medicine, Division of Cardiology, Univ. of Texas-Houston Medical School, 6431 Fannin, MSB 1.246, Houston, TX 77030, USA.
Taegtmeyer
Heinrich
H
Adrogue
Julia
J
Razeghi
Peter
P
Sen
Shiraj
S
Ngumbela
Kholiswa
K
Essop
M Faadiel
MF
D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism* / Q000503:physiopathology*; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009124:Muscle Proteins; D018995:Myosin Heavy Chains / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D012518:Sarcomeres / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*
D005227:Fatty Acids; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D018160:Receptors, Cytoplasmic and Nuclear; C495679:Slc2a1 protein, rat; C495694:Slc2a4 protein, rat; D014157:Transcription Factors; D009320:Atrial Natriuretic Factor; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018995:Myosin Heavy Chains; D000252:Calcium-Transporting ATPases; D005947:Glucose; D002118:Calcium