18
M. A. Asson-Batres
The results from our studies are consistent with ideas that the postnatal heart is
a retinoid responsive tissue. As shown by immunohistological staining, RARγ was
broadly expressed in the nucleus and cytosol of cells present in both the right and left
ventricles. Decreased availability of vitamin A either due to a lack of vitamin A stores
(LRVAS mice) or to decreased stores and circulating levels of vitamin A (LRVAD
mice) impacts genetic programs driven by retinoic acid response elements (RARE)
present in retinoic acid responsive genes. A comparison of gene expression profiles
using an Affymetrix microarray analysis of RNA extracted from the right ventricles
(RV) and left ventricles (LV) of age-matched, LRVAS, LRVAD and wild type vitamin A sufficient (WTVAS) mice identified four differentially-expressed transcripts
encoded by genes with RARE—two that are known to be positively regulated by
retinoic acid were decreased in LRVAD ventricles, and two that are known to be
negatively regulated by retinoic acid or vitamin A status were significantly increased
in both LRVAS and LRVAD mice relative to WTVAS controls. In silico analysis
revealed that 58/67 differentially expressed transcripts were products of genes with
RARE.
Genes without RARE were also affected by the vitamin A status of the heart.
Twenty-eight probes were significantly altered in the RV of LRVAS animals and
31 in the RV of LRVAD mice relative to WTVAS RV controls. Thirty-seven probes
were significantly altered in the LV of LRVAS animals and 50 in the LV of LRVAD
animals relative to WTVAS LV controls.
Having established that genetic deletion of lrat alone was sufficient to induce measureable changes in vitamin A/retinoic acid responses in the heart, we carried out further studies using LRVAS and WTVAS mice. Two interesting changes were recorded:
(1) Flow cytometric analysis revealed a significant and cell-specific increase in the
number of proliferating Sca-1
+ cardiac progenitor cells in LRVAS animals relative
to WTVAS controls, and (2) Prior to myocardial infarction, LRVAS and WTVAS
mice had similar cardiac systolic function and structure as measured by echocardiography, but repeat echocardiography demonstrated that LRVAS mice had less
adverse remodeling by 1 week after myocardial infarction. These outcomes suggest
that even though circulating levels of vitamin A remain unchanged, a reduction in
vitamin A stores is sufficient to signal cardiac progenitor cell populations to increase
and, as well, to improve the heart’s response to injury. The latter finding echoes the
results of Huang et al. who also found that limiting retinoic acid availability improved
outcomes for the recovering heart (Asson-Batres et al. 2016; Huang et al. 2012).
Effects of Vitamin A Deficiency on Other Postnatal Systems
Studies in numerous laboratories continue to confirm and delineate vitamin A’s broad
range of effects on postnatal vertebrate tissues, organs and systems (Wiseman et al.
2017). Much current interest is focused on deciphering the effects of vitamin A on
normal pancreatic and immune functions and the diseases and dysfunctional states
that are impacted by vitamin A deficiency, including diabetes, multiple sclerosis, and
M. A. Asson-Batres
The results from our studies are consistent with ideas that the postnatal heart is
a retinoid responsive tissue. As shown by immunohistological staining, RARγ was
broadly expressed in the nucleus and cytosol of cells present in both the right and left
ventricles. Decreased availability of vitamin A either due to a lack of vitamin A stores
(LRVAS mice) or to decreased stores and circulating levels of vitamin A (LRVAD
mice) impacts genetic programs driven by retinoic acid response elements (RARE)
present in retinoic acid responsive genes. A comparison of gene expression profiles
using an Affymetrix microarray analysis of RNA extracted from the right ventricles
(RV) and left ventricles (LV) of age-matched, LRVAS, LRVAD and wild type vitamin A sufficient (WTVAS) mice identified four differentially-expressed transcripts
encoded by genes with RARE—two that are known to be positively regulated by
retinoic acid were decreased in LRVAD ventricles, and two that are known to be
negatively regulated by retinoic acid or vitamin A status were significantly increased
in both LRVAS and LRVAD mice relative to WTVAS controls. In silico analysis
revealed that 58/67 differentially expressed transcripts were products of genes with
RARE.
Genes without RARE were also affected by the vitamin A status of the heart.
Twenty-eight probes were significantly altered in the RV of LRVAS animals and
31 in the RV of LRVAD mice relative to WTVAS RV controls. Thirty-seven probes
were significantly altered in the LV of LRVAS animals and 50 in the LV of LRVAD
animals relative to WTVAS LV controls.
Having established that genetic deletion of lrat alone was sufficient to induce measureable changes in vitamin A/retinoic acid responses in the heart, we carried out further studies using LRVAS and WTVAS mice. Two interesting changes were recorded:
(1) Flow cytometric analysis revealed a significant and cell-specific increase in the
number of proliferating Sca-1
+ cardiac progenitor cells in LRVAS animals relative
to WTVAS controls, and (2) Prior to myocardial infarction, LRVAS and WTVAS
mice had similar cardiac systolic function and structure as measured by echocardiography, but repeat echocardiography demonstrated that LRVAS mice had less
adverse remodeling by 1 week after myocardial infarction. These outcomes suggest
that even though circulating levels of vitamin A remain unchanged, a reduction in
vitamin A stores is sufficient to signal cardiac progenitor cell populations to increase
and, as well, to improve the heart’s response to injury. The latter finding echoes the
results of Huang et al. who also found that limiting retinoic acid availability improved
outcomes for the recovering heart (Asson-Batres et al. 2016; Huang et al. 2012).
Effects of Vitamin A Deficiency on Other Postnatal Systems
Studies in numerous laboratories continue to confirm and delineate vitamin A’s broad
range of effects on postnatal vertebrate tissues, organs and systems (Wiseman et al.
2017). Much current interest is focused on deciphering the effects of vitamin A on
normal pancreatic and immune functions and the diseases and dysfunctional states
that are impacted by vitamin A deficiency, including diabetes, multiple sclerosis, and