Jm. Wu et al., 1,25(OH)(2) VITAMIN-D-3 AND RETINOIC ACID ANTAGONIZE ENDOTHELIN-STIMULATED HYPERTROPHY OF NEONATAL RAT CARDIAC MYOCYTES, The Journal of clinical investigation, 97(7), 1996, pp. 1577-1588
1,25 (OH)(2) Vitamin D-3 (VD3) and retinoic acid (RA) function as liga
nds for nuclear receptors which regulate transcription, Though the car
diovascular system is not thought to represent a classical target for
these ligands, it is clear that both cardiac myocytes and vascular smo
oth muscle cells respond to these agents with changes in growth charac
teristics and gene expression, In this study we demonstrate that each
of these ligands suppresses many of the phenotypic correlates of endot
helin-induced hypertrophy in a cultured neonatal rat cardiac ventricul
ocyte model, Each of these agents reduced endothelin-stimulated ANP se
cretion in a dose-dependent fashion and the two in combination proved
to be more effective than either agent used alone (VD3: 49%; RA: 52%;
VD3 + RA: 80% inhibition), RA, at concentrations known to activate the
retinoid X receptor, and, to a lesser extent, VD3 effected a reductio
n in atrial natriuretic peptide, brain natriuretic peptide, and alpha-
skeletal actin mRNA levels, Similar inhibition (VD3: 30%; RA: 33%; VD3
+ RA: 59% inhibition) was demonstrated when cells transfected with re
porter constructs harboring the relevant promoter sequences were treat
ed with VD3 and/or RA for 48 h. These effects were not accompanied by
alterations in endothelin-induced c-fos, c-jun, or c-myc gene expressi
on, suggesting either that the inhibitory locus responsible for the re
duction in the mRNA levels lies distal to the activation of the immedi
ate early gene response or that the two are not mechanistically couple
d, Both VD3 and RA also reduced [H-3]leucine incorporation (VD3: 30%;
RA: 33%; VD3 + RA: 45% inhibition) in endothelin-stimulated ventriculo
cytes and, once again, the combination of the two was more effective t
han either agent used in isolation. Finally, 1,25 (OH)(2) vitamin D-3
abrogated the increase in cell size seen after endothelin treatment, T
hese Endings suggest that the liganded vitamin D and retinoid receptor
s are capable of modulating the hypertrophic process in vitro and that
agents acting through these or similar signaling pathways may be of v
alue in probing the molecular mechanisms underlying hypertrophy.