Maternal low-protein diet programs cardiac beta-adrenergic response and signaling in 3-mo-old male offspring
Denise S Fernandez-Twinn1, Sofia Ekizoglou, Adrian Wayman
1Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge, UK. df220@cam.ac.uk
Insights
Low birth weight due to maternal low-protein diet impairs cardiac beta-adrenergic response and insulin signaling in offspring, increasing cardiovascular disease risk. This highlights potential molecular deficiencies predicting heart failure.
Area of Science:
- Cardiovascular Physiology
- Developmental Programming
- Molecular Cardiology
Background:
- Low birth weight is linked to increased cardiovascular disease risk in humans.
- Reduced beta-adrenergic response is observed in heart failure patients.
- Intrauterine undernutrition may predispose offspring to adult metabolic and cardiovascular dysfunction.
Purpose of the Study:
- To investigate the hemodynamic response to isoproterenol in a low-birth weight rodent model.
- To identify molecular changes in beta-adrenergic signaling and insulin pathways in offspring of undernourished mothers.
- To assess if these molecular deficiencies predict cardiac failure risk.
Main Methods:
- Wistar rats were fed control or low-protein diets during pregnancy and lactation.
- Offspring hemodynamics (heart rate, blood pressure) and response to isoproterenol (ISO) infusion were monitored via radiotelemetry.
- Western blot analysis measured protein expression of beta-adrenergic signaling components and insulin receptor-beta.
Main Results:
- Low-protein (LP) offspring exhibited increased basal heart rate but unchanged mean arterial pressure.
- The chronotropic and inotropic responses to isoproterenol were blunted in LP offspring.
- LP offspring showed reduced beta1-adrenergic receptor and insulin receptor-beta expression, with increased beta-arrestin levels.
Conclusions:
- Intrauterine undernutrition via a low-protein diet leads to reduced beta-adrenergic responsiveness in offspring.
- Attenuated adrenergic and insulin signaling pathways are present in low birth weight offspring.
- These findings suggest that intrauterine undernutrition alters molecular pathways, increasing susceptibility to heart failure later in life.
Abstract:
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.
