Zhou M D, Sucov H M, Evans R M, Chien K R
Department of Medicine, University of California, San Diego, School of Medicine, La Jolla 92093, USA.
Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7391-5. doi: 10.1073/pnas.92.16.7391.
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.
利用心肌细胞肥大的体外模型系统，我们确定了一条视黄酸（RA）介导的信号通路，该通路可抑制在暴露于α-肾上腺素能受体激动剂去氧肾上腺素后肥厚表型特定特征的获得。生理浓度的RA可抑制细胞大小的增加以及肥厚的遗传标志物心房利钠因子（ANF）基因的诱导。RA还可抑制心肌细胞肥大的内皮素1信号通路，但不影响血清刺激诱导的细胞大小增加和ANF表达。使用瞬时转染试验进行的反式激活分析表明，新生大鼠心室心肌细胞表达视黄酸受体和类视黄醇X受体（RAR和RXR）亚型的功能性RA受体。使用选择性结合RXR或RAR的RA合成激动剂，我们的数据表明RAR/RXR异二聚体介导对α-肾上腺素能受体依赖性肥大的抑制。这些结果提示体内可能存在抑制肥大的信号通路，这可能具有潜在的治疗价值。
