Mitochondria antioxidant protection against cardiovascular dysfunction programmed by early-onset gestational hypoxia.
Ana-Mishel SpiroskiYouguo NiuLisa M NicholasShani Austin-WilliamsEmily J CammMegan R SutherlandThomas J AshmoreKatie L SkeffingtonAngela LoganSusan E OzanneMichael P MurphyDino A GiussaniPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2021)
Mitochondria-derived oxidative stress during fetal development increases cardiovascular risk in adult offspring of pregnancies complicated by chronic fetal hypoxia. We investigated the efficacy of the mitochondria-targeted antioxidant MitoQ in preventing cardiovascular dysfunction in adult rat offspring exposed to gestational hypoxia, integrating functional experiments in vivo, with those at the isolated organ and molecular levels. Rats were randomized to normoxic or hypoxic (13%-14% O2 ) pregnancy ± MitoQ (500 μM day-1 ) in the maternal drinking water. At 4 months of age, one cohort of male offspring was chronically instrumented with vascular catheters and flow probes to test in vivo cardiovascular function. In a second cohort, the heart was isolated and mounted onto a Langendorff preparation. To establish mechanisms linking gestational hypoxia with cardiovascular dysfunction and protection by MitoQ, we quantified the expression of antioxidant system, β-adrenergic signaling, and calcium handling genes in the fetus and adult, in frozen tissues from a third cohort. Maternal MitoQ in hypoxic pregnancy protected offspring against increased α1 -adrenergic reactivity of the cardiovascular system, enhanced reactive hyperemia in peripheral vascular beds, and sympathetic dominance, hypercontractility and diastolic dysfunction in the heart. Inhibition of Nfe2l2-mediated oxidative stress in the fetal heart and preservation of calcium regulatory responses in the hearts of fetal and adult offspring link molecular mechanisms to the protective actions of MitoQ treatment of hypoxic pregnancy. Therefore, these data show the efficacy of MitoQ in buffering mitochondrial stress through NADPH-induced oxidative damage and the prevention of programmed cardiovascular disease in adult offspring of hypoxic pregnancy.
Keyphrases
- oxidative stress
- pregnancy outcomes
- diabetic rats
- high fat diet
- early onset
- drinking water
- cardiovascular disease
- preterm birth
- pregnant women
- ischemia reperfusion injury
- weight gain
- dna damage
- induced apoptosis
- birth weight
- endothelial cells
- heart failure
- reactive oxygen species
- clinical trial
- atrial fibrillation
- endoplasmic reticulum
- blood pressure
- anti inflammatory
- health risk
- metabolic syndrome
- adipose tissue
- stress induced
- gene expression
- binding protein
- childhood cancer
- physical activity
- transcription factor
- machine learning
- electronic health record
- dna methylation
- study protocol
- insulin resistance
- health risk assessment
- open label
- high resolution
- skeletal muscle
- coronary artery disease
- double blind
- signaling pathway
- fluorescent probe
- high speed
- genome wide identification