Excessive glucocorticoid exposure during late intrauterine development modulates the expression of cardiac uncoupling proteins in adult hypertensive male offspring.
We investigated the impact of intrauterine growth retardation and fetal programming of hypertension by maternal dexamethasone treatment on cardiac uncoupling protein (UCP) expression during development and in adulthood in the rat. Dexamethasone administered via an indwelling osmotic pump (100 micrograms/kg body mass per day from day 15 of gestation) decreased fetal body mass at day 21 of gestation (by 13%; P < 0.05), elicited significant (+24%, P < 0.01) systolic hypertension and elevated corticosterone levels (+15%; P < 0.05) in adult (24-week-old) male offspring. Cardiac UCP-2 and UCP-3 protein expression was significantly upregulated during early postnatal development, reaching 1.7-fold and 2.7-fold the respective fetal day-21 levels by postnatal day 7 and reaching plateaus at postnatal days 15-21 (2.5-fold and 3.5-fold of respective fetal levels). Cardiac UCP protein expression at fetal day 21 and the ontogeny of cardiac UCP expression during early postnatal life were unaffected by prenatal dexamethasone treatment. Prenatal dexamethasone treatment did not abrogate the postnatal surge in corticosterone levels or modify plasma non-esterified fatty acid (NEFA) levels over this period. However, UCP-2 and UCP-3 protein expression was significantly downregulated in the hearts of adult hypertensive male offspring of dexamethasone-treated mothers (to 27% and 65% of control values respectively). We propose that changes in cardiac UCP protein expression are linked with changes in cardiac metabolic fuel selection (from glucose-->fatty acids at birth and from fatty acids-->glucose during hypertension).
Langdown
M L
ML
Department of Diabetes and Metabolic Medicine, Division of General and Developmental Medicine, St. Bartholomew's and the Royal London, School of Medicine and Dentistry, Queen Mary, University of London, London, E1 4NS, UK.
Smith
N D
ND
Sugden
M C
MC
Holness
M J
MJ
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation; D005227:Fatty Acids / Q000097:blood; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced; D005333:Fetus / Q000378:metabolism; D005865:Gestational Age; D005938:Glucocorticoids / Q000494:pharmacology*; D006321:Heart / Q000196:embryology; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D066298:In Vitro Techniques; D007473:Ion Channels; D008297:Male; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D009206:Myocardium / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
D002352:Carrier Proteins; D005227:Fatty Acids; D005938:Glucocorticoids; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; C000604391:Ucp2 protein, rat; C000604394:Ucp3 protein, rat; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D003907:Dexamethasone; D003345:Corticosterone