Research ArticleDEVELOPMENTAL BIOLOGY

Translatable mitochondria-targeted protection against programmed cardiovascular dysfunction

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Science Advances  19 Aug 2020:
Vol. 6, no. 34, eabb1929
DOI: 10.1126/sciadv.abb1929
  • Fig. 1 The mitochondria-targeted antioxidant MitoQ prevents lipid peroxidation without affecting superoxide generation.

    The mitochondrial respiratory chain produces the ROS superoxide (O2•−), much of which is converted to hydrogen peroxide by the action of MnSOD (Mn superoxide dismutase). The superoxide can also react with NO to form peroxynitrite. The hydrogen peroxide can initiate oxidative damage to the mitochondria in the form of lipid peroxidation. The mitochondria-targeted antioxidant MitoQ blocks lipid peroxidation but does not directly affect mitochondrial superoxide production or react to any substantial extent with superoxide.

  • Fig. 2 Effect of MitoQ treatment on the brain-sparing response to acute hypoxia in fetal sheep.

    MitoQ administered intravenously to pregnant ewes at 127 ± 1 days of gestation (term is ca. 145 days) crossed the placenta and accumulated to levels above therapeutic concentrations (dotted line) in the placenta and fetal organs (A). During an episode of acute hypoxia [gray box, (B)] induced 1 hour after maternal MitoQ treatment (vertical line), fetuses exposed to MitoQ (red group, n = 6) compared to saline controls (white group; n = 6) showed similar bradycardia (C) and equivalent responses in carotid (D) and femoral (E) blood flow, oxygen (F and G), and glucose (H and I) delivery. Data in (C) to (E) represent minute averages with associated SEM throughout the experiment, with overlaid statistical analysis from 15-min epochs. (B) and (F) to (I) represent data taken from a blood sample at each time point (means ± SEM). The effect of MitoQ was determined with a repeated-measures ANOVA with time as a repeated factor and the Tukey’s post hoc test, with the exception of (A), where a two-way ANOVA for treatment and organ was performed. (A) † indicates a significant effect of MitoQ. (B to I) * indicates a significant difference compared to baseline. BPM, beats per minute.

  • Fig. 3 Effect of chronic hypoxia and MitoQ treatment in fetal sheep.

    (A) Exposure to chronic hypoxia from 105 to 138 days of gestation (term is ca. 145 days) decreased the maternal PaO2. Fetuses of chronic hypoxic pregnancies (gray) relative to controls (white) had lower fetal body weight (B), increased fetal brain weight–to–body weight ratio (C), and decreased sensitivity of the fetal femoral artery to the NO donor SNP (D and E). Maternal daily intravenous treatment with MitoQ to normoxic (blue) or hypoxic (red) pregnant ewes from 105 to 138 days of gestation resulted in greater than therapeutic concentrations (dotted line) of MitoQ content in the placenta and fetal sheep tissues, with the exception of the fetal brain [(F), main and magnified inset]. Maternal treatment with MitoQ in hypoxic pregnancy restored fetal body weight (B) while maintaining an elevated fetal brain to fetal body weight ratio (C) and protected against the effects of hypoxia on fetal femoral vascular sensitivity to SNP (D and E). Values are means ± SEM. The effect of hypoxia and MitoQ treatment was determined by two-way ANOVA (B, C, and E), with repeated measures where appropriate (A). * indicates a significant effect of hypoxia; † indicates a significant effect of MitoQ. The effect of MitoQ, hypoxia, and organ type in (F) was determined by three-way ANOVA. Organ*Q indicates a significant interaction, with subsequent post hoc Tukey test. Different letters show significantly different contents of MitoQ by organ type.

  • Fig. 4 Effect of chronic hypoxia and MitoQ treatment in the chicken embryo.

    Compared to normoxic embryos (white), incubation of chicken embryos under hypoxia (gray) from 0 to 19 days (term is 21 days) increased hematocrit (A) and caused growth restriction (B). Chronic hypoxia increased mitochondria-derived oxidative stress measured in vivo (conversion of MitoP to MitoB) in the chicken embryo heart (C), decreased the cardiac mitochondrial respiratory control ratio (D), increased the left ventricular lumen to wall ratio (E), reduced the LVDP in an isolated Langendorff preparation (F), and impaired endothelial dependent vasorelaxation to ACh in isolated femoral arteries via in vitro wire myography (G). Treating chicken embryos with MitoQ between days 13 and 18 of incubation resulted in a significant elevation of MitoQ content above therapeutic levels (dotted line) in the fetal heart in both hypoxic (red) and normoxic (blue) groups (H). MitoQ treatment in hypoxic chicken embryos did not affect the elevation in hematocrit or the growth restriction, but it restored all other outcomes (A to G). Values are means ± SEM. The effect of hypoxia and MitoQ treatment was determined by two-way ANOVA, with repeated measures where appropriate (G). * indicates a significant effect of hypoxia; † indicates a significant effect of MitoQ; H*Q indicates a significant interaction, with subsequent post hoc Tukey test. Statistics for (G) reflect comparisons of area above the curve.

  • Fig. 5 Effect of chronic hypoxia and MitoQ treatment on the programming of vascular dysfunction and hypertension in the adult offspring in sheep.

    Compared to controls (white), young adult lambs of hypoxic pregnancy (gray) were hypertensive (A and B) by 9 months. (C and D) Their isolated femoral arteries showed impaired relaxation to SNP (wire myography). Maternal MitoQ treatment in hypoxic pregnancy (red) restored the programmed hypertension (A and B) and improved the SNP femoral relaxation (C and D). Maternal MitoQ in normoxic pregnancy (blue) did not affect arterial pressure or SNP relaxation (A to D). Maternal MitoQ treatment in any pregnancy programmed an increase in basal NO bioavailability in the adult offspring measured in vivo. (E) A greater fall in FVC in response to l-NAME treatment supports this. Maternal MitoQ treatment in any pregnancy also programmed an increase in peripheral vascular sensitivity to NO in the adult offspring in vivo. (F) A greater increment in FVC in response to SNP infusion (gray area) for 30 min supports this. Values are means ± SEM. The effect of hypoxia and MitoQ treatment was determined by two-way ANOVA, with repeated measures where appropriate (C and F). * indicates a significant effect of hypoxia; † indicates a significant effect of MitoQ. T*H*Q indicates significant interaction, with subsequent post hoc Tukey or Students t test. For (F), the average of 15-min epochs is presented for baseline (B1 and B2), SNP (SNP1 and SNP2), and recovery (R1 and R2).

  • Fig. 6 Summary illustration: Protective effects of MitoQ treatment in hypoxic development.

    The mitochondria-targeted antioxidant MitoQ protects the chronically hypoxic fetus from cardiovascular dysfunction and remodeling, which programs adult-onset peripheral vascular dysfunction and systemic hypertension. These protective effects of MitoQ in the compromised fetus occur without affecting the fetal brain–sparing hemodynamic response to acute hypoxia. Mechanisms underlying benefits of MitoQ on the offspring cardiovascular system include direct protection against mitochondria-derived oxidative stress and normalization of cardiac mitochondrial respiration in the hypoxic embryo, together with programmed increases in circulating NO bioavailability and in peripheral vascular sensitivity to it in the adult offspring. MitoQ treatment in sheep protects against fetal growth restriction in hypoxic pregnancy. In contrast, MitoQ treatment in hypoxic chicken embryos does not affect growth restriction. Therefore, protective effects of MitoQ on fetal growth in mammals may occur at the level of the placenta.

Supplementary Materials

  • Supplementary Materials

    Translatable mitochondria-targeted protection against programmed cardiovascular dysfunction

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

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