Maternal allopurinol prevents cardiac dysfunction in adult Male offspring programmed by chronic hypoxia during pregnancy

Youguo Niu, Andrew D. Kane, Ciara M. Lusby, Beth J. Allison, Yi Yi Chua, Joepe J. Kaandorp, Rhiannon Nevin-Dolan, Thomas J. Ashmore, Heather L. Blackmore, Jan B. Derks, Susan E. Ozanne, Dino A. Giussani

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14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)971-978
Number of pages8
JournalHypertension
Volume72
Issue number4
DOIs
Publication statusPublished - 1 Jan 2018
Externally publishedYes

Keywords

  • Allopurinol developmental programming hypoxia oxidative stress pregnancy rats

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