Retinoid-dependent pathways suppress myocardial cell hypertrophy.
Utilizing an in vitro model system of cardiac muscle cell hypertrophy, we have identified a retinoic acid (RA)-mediated pathway that suppresses the acquisition of specific features of the hypertrophic phenotype after exposure to the alpha-adrenergic receptor agonist phenylephrine. RA at physiological concentrations suppresses the increase in cell size and induction of a genetic marker for hypertrophy, the atrial natriuretic factor (ANF) gene. RA also suppresses endothelin 1 pathways for cardiac muscle cell hypertrophy, but it does not affect the increase in cell size and ANF expression induced by serum stimulation. A trans-activation analysis using a transient transfection assay reveals that neonatal rat ventricular myocardial cells express functional RA receptors of both the retinoic acid receptor and retinoid X receptor (RAR and RXR) subtypes. Using synthetic agonists of RA, which selectively bind to RXR or RAR, our data indicate that RAR/RXR heterodimers mediate suppression of alpha-adrenergic receptor-dependent hypertrophy. These results suggest the possibility that a pathway for suppression of hypertrophy may exist in vivo, which may have potential therapeutic value.
Zhou
M D
MD
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla 92093, USA.
Sucov
H M
HM
Evans
R M
RM
Chien
K R
KR
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D048429:Cell Size / Q000187:drug effects; D016232:Endothelins / Q000378:metabolism; D005819:Genetic Markers; D006321:Heart / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047488:Retinoid X Receptors; D012176:Retinoids / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology
D016232:Endothelins; D005819:Genetic Markers; D011942:Receptors, Adrenergic, alpha; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; D010656:Phenylephrine; D014212:Tretinoin; D009320:Atrial Natriuretic Factor