Maternal Allopurinol Prevents Cardiac Dysfunction in Adult Male Offspring Programmed by Chronic Hypoxia During Pregnancy.
Authors
Niu, Youguo
Kane, Andrew D
Lusby, Ciara M
Allison, Beth J
Chua, Yi Yi
Kaandorp, Joepe J
Nevin-Dolan, Rhiannon
Ashmore, Thomas J
Blackmore, Heather L
Derks, Jan B
Ozanne, Susan E
Giussani, Dino A
Publication Date
2018-10Journal Title
Hypertension
ISSN
0194-911X
Publisher
Ovid Technologies (Wolters Kluwer Health)
Volume
72
Issue
4
Pages
971-978
Language
eng
Type
Article
Physical Medium
Print
Metadata
Show full item recordCitation
Niu, Y., Kane, A. D., Lusby, C. M., Allison, B. J., Chua, Y. Y., Kaandorp, J. J., Nevin-Dolan, R., et al. (2018). Maternal Allopurinol Prevents Cardiac Dysfunction in Adult Male Offspring Programmed by Chronic Hypoxia During Pregnancy.. Hypertension, 72 (4), 971-978. https://doi.org/10.1161/HYPERTENSIONAHA.118.11363
Abstract
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.
Keywords
Sympathetic Nervous System, Animals, Rats, Pregnancy Complications, Allopurinol, Xanthine Oxidase, Receptors, Adrenergic, beta, Receptor, Muscarinic M2, Enzyme Inhibitors, Heart Function Tests, Oxidative Stress, Pregnancy, Myocardial Contraction, Female, Male, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Heart Failure, Hypoxia
Sponsorship
British Heart Foundation
Funder references
British Heart Foundation (None)
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)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1161/HYPERTENSIONAHA.118.11363
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279642
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