TY - JOUR
T1 - Maternal allopurinol prevents cardiac dysfunction in adult Male offspring programmed by chronic hypoxia during pregnancy
AU - Niu, Youguo
AU - Kane, Andrew D.
AU - Lusby, Ciara M.
AU - Allison, Beth J.
AU - Chua, Yi Yi
AU - Kaandorp, Joepe J.
AU - Nevin-Dolan, Rhiannon
AU - Ashmore, Thomas J.
AU - Blackmore, Heather L.
AU - Derks, Jan B.
AU - Ozanne, Susan E.
AU - Giussani, Dino A.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
KW - Allopurinol developmental programming hypoxia oxidative stress pregnancy rats
UR - http://www.scopus.com/inward/record.url?scp=85055606216&partnerID=8YFLogxK
U2 - 10.1161/HYPERTENSIONAHA.118.11363
DO - 10.1161/HYPERTENSIONAHA.118.11363
M3 - Article
C2 - 30354714
AN - SCOPUS:85055606216
SN - 0194-911X
VL - 72
SP - 971
EP - 978
JO - Hypertension
JF - Hypertension
IS - 4
ER -