Coenzyme Q10 prevents accelerated cardiac aging in a rat model of poor maternal nutrition and accelerated postnatal growth

Abstract

Studies in human and animals have demonstrated that nutritionally induced low birth-weight followed by rapid postnatal growth increases the risk of metabolic syndrome and cardiovascular disease. Although the mechanisms underlying such nutritional programming are not clearly defined, increased oxidative-stress leading to accelerated cellular aging has been proposed to play an important role. Using an established rodent model of low birth-weight and catch-up growth, we show here that post-weaning dietary supplementation with coenzyme Q10, a key component of the electron transport chain and a potent antioxidant rescued many of the detrimental effects of nutritional programming on cardiac aging. This included a reduction in nitrosative and oxidative-stress, telomere shortening, DNA damage, cellular senescence and apoptosis. These findings demonstrate the potential for postnatal antioxidant intervention to reverse deleterious phenotypes of developmental programming and therefore provide insight into a potential translatable therapy to prevent cardiovascular disease in at risk humans.

Keywords: 3-NT, 3-nitrotyrosine; 4-HNE, 4-hydroxynonenal; BER, base excision repair; Bax, Bcl2-associated protein; CAST, computer assisted stereology toolbox.; CVD, cardiovascular disease; Cellular senescence; CoQ, coenzyme Q; CuZnSOD, copper-zinc superoxide dismutase; DIG, dioxygenin; DNA damage; Developmental programming; ETC, electron transport chain; GPx, glutathione peroxidase; GR, glutathione reductase; MnSOD, manganese superoxide dismutase; NEIL1, nei endonuclease VIII-like 1; NOX, nicotinamide adenine dinucleotide diphosphate oxidase; NTHL1, Nthl endonuclease III like-1; O2, superoxide anion; OGG-1, 8 oxoguanine DNA glycosylase 1; OH-, hydroxy radicals; Oxidative-stress; PGFE, pulsed field gel electrophoresis; PRDX, peroxidiredoxin; RIS, reactive inflammatory species; RNS, reactive nitrogen species; ROS, reactive oxidative species; Telomere length; Ubiquinone; XO, xanthine oxidase; acta1, sarco endoplasmic reticulum Ca(2+) ATPase; actin, alpha-1; nppa, natriuretic peptide A; nppb, natriuretic peptide B; serca2, single strand breaks, SSBs.

Graphical abstract

Figure 1

The effect of in-utero protein restriction and accelerated postnatal growth upon cardiac and plasma CoQ₉ and CoQ₁₀ levels in 3 and 12 month rat hearts. CoQ₉ and CoQ₁₀ levels were measured using HPLC. Results are expressed as mean±S.E.M. * p<0.05 and ** p<0.01 compared to control/recuperated CoQ. (N=10 per group). C=control; CQ=control CoQ; R=recuperated and RQ=recuperated CoQ. (See also Supplementary Figure 1). (A) Plasma CoQ₁₀, (B) Cardiac CoQ₉ and CoQ₁₀.

Figure 2

The effect of in-utero protein restriction and accelerated postnatal growth upon telomere length in 3 and 12 month rat hearts. Telomere length was measured using Pulsed Field Gel Electrophoresis (PGFE) and Southern Blotting. Results are expressed as mean±S.E.M. * p<0.05 and ** p<0.01 compared to control/recuperated CoQ. N=6 per group; C=control; CQ=control CoQ; R=recuperated and RQ=recuperated CoQ. (A) 3 months and (B) 12 months.

Figure 3

The effect of in-utero protein restriction and accelerated postnatal growth upon 3-NT, XO and p47^phox levels in 3 and 12 month rat hearts. 3-NT and 4-HNE levels were measured using ELISA. XO and p47^phox protein expressions were analyzed using Western blotting. Results are expressed as mean±S.E.M. * p<0.05 and *** p<0.001 compared to control/recuperated CoQ. N=10 per group (3-NT and 4-HNE levels). N=6 per group (XO protein expression). C=control; CQ=control CoQ; R=recuperated and RQ=recuperated CoQ. (See also Supplementary Figure 2). (A) 3-NT, (B) XO and (C) p47^phox.

Figure 4

The effect of in-utero protein restriction and accelerated postnatal growth upon expression of DNA repair enzymes in 3 and 12 month rat hearts. Protein expression was analyzed using Western blotting. Results are expressed as mean±S.E.M. * p<0.05 and *** p<0.001 compared to control/recuperated CoQ. N=6 per group. C=control; CQ=control CoQ; R=recuperated and RQ=recuperated CoQ. (See also Supplementary Figure 3). (A) OGG1 and (B) NTHL1.

Figure 5

The effect of in-utero protein restriction and accelerated postnatal growth upon antioxidant protein expression in 3 and 12 month rat hearts. Protein expression was analyzed using Western blotting. Results are expressed as mean±S.E.M. * p<0.05, ** p<0.01 and *** p<0.001 compared to control/recuperated CoQ. N=6 per group. C=control; CQ=control CoQ; R=recuperated and RQ=recuperated CoQ. (A) MnSOD, (B) CuZnSOD (12 months), (C) Catalase, (D) HO-1 (12 months), (E) PRDX3 (12 months) and (F) GPx1 (12 months).

Figure 6

The effect of in-utero protein restriction and accelerated postnatal growth upon apoptosis and senescence marker protein expression in 3 and 12 month rat hearts. Protein expression was analyzed using Western blotting. Results are expressed as mean±S.E.M. * p<0.05, ** p<0.01 and *** p<0.001 compared to control/recuperated CoQ. N=6 per group. C=control; CQ=control CoQ; R=recuperated and RQ=recuperated CoQ. (See also Supplementary Figure 4). (A) (i) p53 (12 months), (ii) p21 (12 months), Caspase 3 (12 months) and (B) Bax /Bcl2.

Figure 7

The effect of in-utero protein restriction and accelerated postnatal growth upon fetal cardiac genes in 3 and 12 month rat hearts. Fetal cardiac genes were measured by RT-PCR. Results are expressed as mean±S.E.M. * p<0.05 and ** p<0.01 compared to control/recuperated CoQ. N=10 per group. C=control; CQ=control CoQ; R=recuperated and RQ=recuperated CoQ. (A) Myh7/Myh6, (B) Nppb and (C) GATA4.