1,25 (OH)(2) vitamin D-3 and retinoic acid antagonize endothelin-stimulated hypertrophy of neonatal rat cardiac myocytes
1,25 (OH)(2) vitamin D-3 and retinoic acid antagonize endothelin-stimulated hypertrophy of neonatal rat cardiac myocytes
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DOI：
10.1172/jci118582
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发表时间：
1996-04-01
影响因子：
15.9
通讯作者：
Gardner, DG
中科院分区：
文献类型：
--
作者：
Wu, JM;Garami, M;Gardner, DG
1，25(OH)(2)维生素D-3(VD3)和维甲酸(RA)作为核受体的配体调节转录，尽管心血管系统不被认为是这些配体的经典靶点，但很明显，心肌细胞和血管平滑肌细胞对这些药物的生长特性和基因表达的改变做出了反应。在本研究中，我们证明了这些配体中的每一种都抑制了培养的新生大鼠心肌细胞模型中内皮素诱导的心肌细胞肥大的许多表型相关因素。这些药物中的每一种都以剂量依赖的方式减少内皮素刺激的ANP分泌，并且两种药物联合使用被证明比单独使用任何一种药物都更有效(VD3：49%；RA：52%；VD3+RA：80%抑制)，RA，在已知的激活维甲酸X受体的浓度，以及，在较小程度上，VD3影响心钠素、脑利钠肽和α-骨骼肌动蛋白mRNA水平的降低，类似的抑制(VD3：30%；RA：33%；VD3和/或RA处理48h后，发现VD3和/或RA对c-fos、c-jun或c-myc基因的表达无明显影响，提示导致c-fos、c-jun或c-myc基因表达下降的抑制位点位于即刻早期基因反应激活的远端，或者两者不是机械偶联的，VD3和RA也都减少了[H-3]亮氨酸的掺入(VD3：30%；RA：33%；VD3+RA：45%抑制)，并且，再一次，两种药物的组合比单独使用任何一种药物更有效。最后，1，25(OH)(2)维生素D-3抑制了内皮素治疗后细胞大小的增加，这些结果表明，连接的维生素D和维甲酸受体在体外能够调节肥大过程，通过这些或类似的信号通路作用的药物在探索肥厚的分子机制方面可能有价值。
1,25 (OH)(2) Vitamin D-3 (VD3) and retinoic acid (RA) function as ligands for nuclear receptors which regulate transcription, Though the cardiovascular system is not thought to represent a classical target for these ligands, it is clear that both cardiac myocytes and vascular smooth muscle cells respond to these agents with changes in growth characteristics and gene expression, In this study we demonstrate that each of these ligands suppresses many of the phenotypic correlates of endothelin-induced hypertrophy in a cultured neonatal rat cardiac ventriculocyte model, Each of these agents reduced endothelin-stimulated ANP secretion 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 reduction 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 reporter constructs harboring the relevant promoter sequences were treated 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 expression, suggesting either that the inhibitory locus responsible for the reduction in the mRNA levels lies distal to the activation of the immediate early gene response or that the two are not mechanistically coupled, Both VD3 and RA also reduced [H-3]leucine incorporation (VD3: 30%; RA: 33%; VD3 + RA: 45% inhibition) in endothelin-stimulated ventriculocytes and, once again, the combination of the two was more effective than either agent used in isolation. Finally, 1,25 (OH)(2) vitamin D-3 abrogated the increase in cell size seen after endothelin treatment, These Endings suggest that the liganded vitamin D and retinoid receptors are capable of modulating the hypertrophic process in vitro and that agents acting through these or similar signaling pathways may be of value in probing the molecular mechanisms underlying hypertrophy.