Maternal low-protein diet programs cardiac beta-adrenergic response and signaling in 3-mo-old male offspring.
Low birth weight in humans is associated with an increased risk of cardiovascular disease. Humans with heart failure have a reduced beta-adrenergic response. The aim of this study was to investigate the hemodynamic response to the beta-adrenergic agonist isoproterenol and to identify molecular deficiencies that may be predictive of cardiac failure in a low-birth weight rodent model that develops insulin resistance and type 2 diabetes in adulthood. Wistar rats were fed a control or a low-protein (LP) diet throughout pregnancy and lactation. The resting heart rate and blood pressure of the 3-mo-old male offspring of these dams, termed "control" and "LP" groups, respectively, and their responses to isoproterenol (ISO) infusion were monitored by radiotelemetry. The protein expression of beta-adrenergic signaling components was also measured by Western blot analysis. Basal heart rate was increased in LP offspring (P<0.04), although mean arterial pressure was comparable with controls. Chronotropic effects of ISO were blunted in LP offspring with significant delays to maximal response (P=0.01), a shorter duration of response (P=0.03), and a delayed return to baseline (P=0.01) at the lower dose (0.1 microg.kg-1.min-1). At the higher dose (1.0 microg.kg-1.min-1 ISO), inotropic response was blunted (P=0.03) but quicker (P=0.001). In heart tissue of LP offspring, beta1-adrenergic receptor expression was reduced (P<0.03). beta1-Adrenergic receptor kinase and both stimulatory and inhibitory G protein levels remained unchanged, whereas beta-arrestin levels were higher (P<0.03). Finally, insulin receptor-beta expression was reduced in LP offspring (P<0.012). LP offspring have reduced beta-adrenergic responsiveness and attenuated adrenergic and insulin signaling, suggesting that intrauterine undernutrition alters heart failure risk.
Fernandez-Twinn
Denise S
DS
Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge, UK. df220@cam.ac.uk
Ekizoglou
Sofia
S
Wayman
Adrian
A
Petry
Clive J
CJ
Ozanne
Susan E
SE
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D018753:Diet, Protein-Restricted; D004837:Epinephrine / Q000378:metabolism*; D005260:Female; D054770:G-Protein-Coupled Receptor Kinase 3; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006321:Heart / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007230:Infant, Low Birth Weight / Q000378:metabolism* / Q000502:physiology; D007231:Infant, Newborn; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction; D051552:beta-Adrenergic Receptor Kinases / Q000378:metabolism; D000071557:beta-Arrestins
D019390:Arrestins; D011943:Receptors, Adrenergic, beta; D000071557:beta-Arrestins; D054770:G-Protein-Coupled Receptor Kinase 3; C517848:GRK3 protein, human; C517851:Grk3 protein, rat; D051552:beta-Adrenergic Receptor Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D004837:Epinephrine