Translatable mitochondria-targeted protection against programmed cardiovascular dysfunction.

K J Botting,N Itani,A Logan,K L Skeffington,K L Brain,D A Giussani,A J Murray,B J Allison,M P Murphy,Y Niu,C Beck

doi:10.1126/sciadv.abb1929

K J Botting, N Itani + Show 9 more

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https://doi.org/10.1126/sciadv.abb1929

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Abstract

The prenatal origins of heart disease in offspring have been established. However, research in species with developmental milestones comparable to humans is lacking, preventing translation of this knowledge to clinical contexts. Using sheep and chickens, two species with similar cardiovascular developmental milestones to humans, we combined in vivo experiments with in vitro studies at organ, cellular, mitochondrial, and molecular levels. We tested mitochondria-targeted antioxidant intervention with MitoQ against cardiovascular dysfunction programmed by developmental hypoxia, a common complication in human pregnancy. Experiments in sheep determined in vivo fetal and adult cardiovascular function through surgical techniques not possible in humans, while those in chicken embryos isolated effects independent of maternal or placental influences. We show that hypoxia generates mitochondria-derived oxidative stress during cardiovascular development, programming endothelial dysfunction and hypertension in adult offspring. MitoQ treatment during hypoxic development protects against this cardiovascular risk via enhanced nitric oxide signaling, offering a plausible intervention strategy.

Highlights

Despite improved understanding and advances in treatment, cardio vascular disease still claims the life of one in three people and costs the United States and Canada US$130 billion and the United Kingdom over £30 billion every year (1, 2)
In response to acute hypoxia at 127 ± 1 days of gesta tion in the chronically instrumented sheep fetus, lowering the fetal PaO2 in the descending aorta to 10 to 12 mmHg (Fig. 2B and table S1A), there was a fall in fetal pH and in fetal heart rate, an increase in carotid blood flow, and a fall in femoral blood flow (Fig. 2, C to E)
By addressing questions at the in vivo, isolated organ, cellular, mitochondrial, and molecular levels and exploiting the strength of two animal models, we provide a comprehensive approach to understanding the mechanisms linking MitoQ protection against fetal growth restriction and programmed cardiovascular dysfunction in offspring following development complicated by chronic hypoxia

Summary

INTRODUCTION

Despite improved understanding and advances in treatment, cardio vascular disease still claims the life of one in three people and costs the United States and Canada US$130 billion and the United Kingdom over £30 billion every year (1, 2). Whether MitoQ treatment in development complicated by chronic hypoxia protects the fetus from oxidative stress and the adult offspring from programmed hy pertension in animal models of similar developmental milestones to humans is unknown. We have combined experiments in pregnant sheep and in the chicken embryo, both species of comparable temporal cardiovascular development to humans (11, 21), to determine whether MitoQ (i) crosses the placenta and maintains fetal brain sparing, (ii) protects against fetal growth restriction and programmed adult-onset hypertension in the offspring of hypoxic pregnancy, and (iii) directly protects against fetal mitochondria-derived oxidative stress, mea sured in vivo using a mitochondria-targeted ratiometric mass spec trometry probe (22)

RESULTS

DISCUSSION

MATERIALS AND METHODS

Experiments in sheep

Experiments in the chicken embryo