1 How Dietary Deficiency Studies Have Illuminated the Many Roles …
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involvement of vitamin A/retinoic acid in long-term potentiation (LTP) and longterm depression (LTD), two functional indicators of synaptic plasticity. For these
latter studies, wild type mice were fed a diet lacking a source of vitamin A. The vitamin A deficient mice showed neither tissue degeneration nor changes in postsynaptic
responses, but did exhibit a significant reduction in hippocampal LTP and an almost
complete loss of LTD. Both replenishment of the vitamin A deficient mice with a
dietary source of vitamin A and direct application of retinoic acid to hippocampal
tissue slices reversed the adverse effects of vitamin A deficiency on LTP and LTD.
The investigators concluded that vitamin A acts as a “competence factor” to promote
activation of key target genes that encode proteins required for LTP and LTD (Misner
et al. 2001).
The Cardiovascular System
The cardiovascular system is the first functional system to develop in the embryo,
and a lack of adequate vitamin A disrupts this process. Vitamin A deficient avian
embryos die at embryonic day 4 with grossly abnormal cardiovascluar systems that
lack an inflow tract and a normal vasculature (Zile 2010; Dersch and Zile 1993).
It is now established that retinoic acid is the bioactive derivative of vitamin A that
is required for normal cardiovascular development (Moss et al. 1998). Mice with a
disrupted RALDH2 gene are retinoic acid deficient and display a phenotype similar
to the vitamin A deficient quail embryo. The hearts of RALDH2
−/− mice do not
loop correctly, and both sinoatrial growth and ventricular trabeculation are defective.
These animals die on day 10.5 due to impaired blood circulation (Niederreither et al.
2001).
The postnatal mouse heart continues to express markers of retinoid metabolism
and signaling throughout life, including enzymes that convert vitamin A to retinoic
acid (RALDH2), and nuclear receptor proteins that are activated by retinoic acid
(RARα, RARβ, and RARγ) (Asson-Batres et al. 2016; Bilbija et al. 2012). The role of
retinoids in normal cardiovascular health is still uncertain, but several studies suggest
that injury of the myocardium changes retinoid homeostasis with consequences for
myocardial repair (Bilbija et al. 2014; Huang et al. 2012; Minicucci et al. 2010;
Asson-Batres et al. 2016).
To investigate the role vitamin A plays in postnatal heart health, we carried out
studies with mice lacking the lecithin retinyl acyl transferase (lrat) gene which
encodes an enzyme that catalyzes retinol esterification, the storage form of vitamin
A (Asson-Batres et al. 2016). Knocking out this gene prevents animals from storing
vitamin A reserves and makes them primarily dependent upon their diet to provide
the essential nutrient. Neither LRAT
−/− mice fed a vitamin A sufficient (LRVAS) diet
nor LRAT
−/− mice fed a vitamin A deficient diet (LRVAD) for 50 days exhibited
hallmark symptoms of frank vitamin A deficiency, such as decreased growth rate
alopecia, or ataxia, and thus both experimental groups can be considered to have
been in a depleted, but not completely deficient, state of vitamin A deficiency.
17
involvement of vitamin A/retinoic acid in long-term potentiation (LTP) and longterm depression (LTD), two functional indicators of synaptic plasticity. For these
latter studies, wild type mice were fed a diet lacking a source of vitamin A. The vitamin A deficient mice showed neither tissue degeneration nor changes in postsynaptic
responses, but did exhibit a significant reduction in hippocampal LTP and an almost
complete loss of LTD. Both replenishment of the vitamin A deficient mice with a
dietary source of vitamin A and direct application of retinoic acid to hippocampal
tissue slices reversed the adverse effects of vitamin A deficiency on LTP and LTD.
The investigators concluded that vitamin A acts as a “competence factor” to promote
activation of key target genes that encode proteins required for LTP and LTD (Misner
et al. 2001).
The Cardiovascular System
The cardiovascular system is the first functional system to develop in the embryo,
and a lack of adequate vitamin A disrupts this process. Vitamin A deficient avian
embryos die at embryonic day 4 with grossly abnormal cardiovascluar systems that
lack an inflow tract and a normal vasculature (Zile 2010; Dersch and Zile 1993).
It is now established that retinoic acid is the bioactive derivative of vitamin A that
is required for normal cardiovascular development (Moss et al. 1998). Mice with a
disrupted RALDH2 gene are retinoic acid deficient and display a phenotype similar
to the vitamin A deficient quail embryo. The hearts of RALDH2
−/− mice do not
loop correctly, and both sinoatrial growth and ventricular trabeculation are defective.
These animals die on day 10.5 due to impaired blood circulation (Niederreither et al.
2001).
The postnatal mouse heart continues to express markers of retinoid metabolism
and signaling throughout life, including enzymes that convert vitamin A to retinoic
acid (RALDH2), and nuclear receptor proteins that are activated by retinoic acid
(RARα, RARβ, and RARγ) (Asson-Batres et al. 2016; Bilbija et al. 2012). The role of
retinoids in normal cardiovascular health is still uncertain, but several studies suggest
that injury of the myocardium changes retinoid homeostasis with consequences for
myocardial repair (Bilbija et al. 2014; Huang et al. 2012; Minicucci et al. 2010;
Asson-Batres et al. 2016).
To investigate the role vitamin A plays in postnatal heart health, we carried out
studies with mice lacking the lecithin retinyl acyl transferase (lrat) gene which
encodes an enzyme that catalyzes retinol esterification, the storage form of vitamin
A (Asson-Batres et al. 2016). Knocking out this gene prevents animals from storing
vitamin A reserves and makes them primarily dependent upon their diet to provide
the essential nutrient. Neither LRAT
−/− mice fed a vitamin A sufficient (LRVAS) diet
nor LRAT
−/− mice fed a vitamin A deficient diet (LRVAD) for 50 days exhibited
hallmark symptoms of frank vitamin A deficiency, such as decreased growth rate
alopecia, or ataxia, and thus both experimental groups can be considered to have
been in a depleted, but not completely deficient, state of vitamin A deficiency.