Maternal Allopurinol Prevents Cardiac Dysfunction in Adult Male Offspring Programmed by Chronic Hypoxia During Pregnancy.
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Integrating functional and molecular levels, we investigated the effects of maternal treatment with a xanthine oxidase inhibitor on the programming of cardiac dysfunction in adult offspring using an established rat model of hypoxic pregnancy. Female Wistar rats were divided into normoxic or hypoxic (13% O2) pregnancy±maternal allopurinol treatment (30 mg kg-1 d-1). At 4 months, hearts were isolated from 1 male per litter per outcome variable to determine cardiac function and responses to ischemia-reperfusion in a Langendorff preparation. Sympathetic dominance, perfusate CK (creatine kinase) and LDH (lactate dehydrogenase) and the cardiac protein expression of the β1-adrenergic receptor, the M2 Ach receptor (muscarinic type-2 acetylcholine receptor), and the SERCA2a (sarcoplasmic reticulum Ca2+ ATPase 2a) were determined. Relative to controls, offspring from hypoxic pregnancy showed elevated left ventricular end diastolic pressure (+34.7%), enhanced contractility (dP/dtmax, +41.6%), reduced coronary flow rate (-21%) and an impaired recovery to ischemia-reperfusion (left ventricular diastolic pressure, area under the curve recovery -19.1%; all P<0.05). Increased sympathetic reactivity (heart rate, +755.5%; left ventricular diastolic pressure, +418.9%) contributed to the enhanced myocardial contractility ( P<0.05). Perfusate CK (+431%) and LDH (+251.3%) and the cardiac expression of SERCA2a (+71.4%) were also elevated ( P<0.05), further linking molecular markers of cardiac stress and injury to dysfunction. Maternal allopurinol restored all functional and molecular indices of cardiac pathology. The data support a link between xanthine oxidase-derived oxidative stress in hypoxic pregnancy and cardiac dysfunction in the adult offspring, providing a target for early intervention in the developmental programming of heart disease.
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1524-4563
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British Heart Foundation (None)
British Heart Foundation (None)
Isaac Newton Trust (MINUTE 544(I))
Lister Institute of Preventive Medicine (unknown)
Wellcome Trust (072256/Z/03/Z)
Sir Jules Thorn Charitable Trust (05SC/06A)
Biotechnology and Biological Sciences Research Council (BB/E002668/1)
British Heart Foundation (None)
The Royal Society (wm062239)
British Heart Foundation (None)
British Heart Foundation (None)
Wellcome Trust (072256/Z/03/A)
Wellcome Trust (089941/Z/09/A)
Lister Institute of Preventive Medicine (unknown)
British Heart Foundation (RG/17/8/32924)
British Heart Foundation (None)
Medical Research Council (MC_UU_12012/4)
MRC (MC_UU_00014/4)
Medical Research Council (MC_PC_12012)