Translatable mitochondria-targeted protection against programmed cardiovascular dysfunction

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.

Working towards precision medicine in developmental programming

“…Consequently, there has been an exponential growth of studies in this field of developmental programming aiming to identify underlying mechanisms and thereby treatment, most recently focussed on improving precision medicine by applying basic principles of personalized medicine to intrauterine therapy. 3 Two relevant examples are provided by studies aiming to improve organelle-targeted therapy [4][5][6] and by the growing awareness that the sex of the offspring and of its placenta ought to be included as biological variables into experimental design and analysis when studying vertebrate animals and humans. [7][8][9] A cluster of recent studies has aimed to improve precision intrauterine medicine by employing mitochondria-targeted, rather than conventional, antioxidants to protect against cardiovascular dysfunction programmed in offspring by chronic fetal hypoxia, one of the most common complications in human pregnancy.…”

“…[7][8][9] A cluster of recent studies has aimed to improve precision intrauterine medicine by employing mitochondria-targeted, rather than conventional, antioxidants to protect against cardiovascular dysfunction programmed in offspring by chronic fetal hypoxia, one of the most common complications in human pregnancy. [4][5][6] An interesting discussion is brewing comparing mitochondriatargeted antioxidant therapy directly to the fetus, or treatment specifically to the placenta. Studies using the chicken embryo show that direct in ovo administration of the mitochondriatargeted antioxidant MitoQ prevented in vivo mitochondriaderived oxidative stress and protected against cardiac mitochondrial dysfunction, and impaired cardiac and endothelial function in the chronically hypoxic chicken embryo.…”

“…Studies using the chicken embryo show that direct in ovo administration of the mitochondriatargeted antioxidant MitoQ prevented in vivo mitochondriaderived oxidative stress and protected against cardiac mitochondrial dysfunction, and impaired cardiac and endothelial function in the chronically hypoxic chicken embryo. 4 Further, studies in sheep show that maternal systemic treatment with MitoQ crosses the placenta, increases MitoQ uptake into the fetal tissues, and prevents programmed hypertension in the adult offspring. 4 Combined, therefore, studies in the chicken embryo and in the sheep show that mitochondria-targeted therapy to the hypoxic fetus prevents programmed cardiovascular disease in the adult offspring.…”

“…4 Further, studies in sheep show that maternal systemic treatment with MitoQ crosses the placenta, increases MitoQ uptake into the fetal tissues, and prevents programmed hypertension in the adult offspring. 4 Combined, therefore, studies in the chicken embryo and in the sheep show that mitochondria-targeted therapy to the hypoxic fetus prevents programmed cardiovascular disease in the adult offspring. 4 Conversely, there have been recent studies in rats, which have developed a placenta-targeted treatment strategy using MitoQ encapsulated into nanoparticles (nMitoQ).…”

“…4 Combined, therefore, studies in the chicken embryo and in the sheep show that mitochondria-targeted therapy to the hypoxic fetus prevents programmed cardiovascular disease in the adult offspring. 4 Conversely, there have been recent studies in rats, which have developed a placenta-targeted treatment strategy using MitoQ encapsulated into nanoparticles (nMitoQ). The aim is to protect against placental oxidative stress while preventing passage of the prenatal therapy into the fetal circulation, thereby avoiding potential adverse off-target effects on the fetus.…”