OBJECTIVE Retinoic acid (RA) is a ligand for nuclear receptors that modulate gene transcription and cell differentiation. Whether RA controls ectopic calcification in humans is unknown. We tested the hypothesis that RA regulates osteogenic differentiation of human arterial smooth muscle cells and aortic valvular interstitial cells that participate in atherosclerosis and heart valve disease, respectively. Approach and Results: Human cardiovascular tissue contains immunoreactive RAR (RA receptor)-a retinoid-activated nuclear receptor directing multiple transcriptional programs. RA stimulation suppressed primary human cardiovascular cell calcification while treatment with the RAR inhibitor AGN 193109 or RARα siRNA increased calcification. RA attenuated calcification in a coordinated manner, increasing levels of the calcification inhibitor MGP (matrix Gla protein) while decreasing calcification-promoting TNAP (tissue nonspecific alkaline phosphatase) activity. Given that nuclear receptor action varies as a function of distinct ligand structures, we compared calcification responses to cyclic retinoids and the acyclic retinoid peretinoin. Peretinoin suppressed human cardiovascular cell calcification without inducing either secretion of APOC3 (apolipoprotein-CIII), which promotes atherogenesis, or reducing CYP7A1 (cytochrome P450 family 7 subfamily A member 1) expression, which occurred with cyclic retinoids all-trans RA, 9-cis RA, and 13-cis RA. Additionally, peretinoin did not suppress human femur osteoblast mineralization, whereas all-trans RA inhibited osteoblast mineralization. CONCLUSIONS These results establish retinoid regulation of human cardiovascular calcification, provide new insight into mechanisms involved in these responses, and suggest selective retinoid modulators, like acyclic retinoids may allow for treating cardiovascular calcification without the adverse effects associated with cyclic retinoids.

中文翻译：

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类视黄醇可抑制人类心血管细胞钙化，有证据表明其具有独特的选择性视黄醇调节剂作用。


目的 视黄酸 (RA) 是调节基因转录和细胞分化的核受体的配体。 RA 是否控制人类异位钙化尚不清楚。我们测试了以下假设：RA 调节人动脉平滑肌细胞和主动脉瓣膜间质细胞的成骨分化，分别参与动脉粥样硬化和心脏瓣膜疾病。方法和结果：人类心血管组织含有免疫反应性 RAR（RA 受体）——一种指导多个转录程序的视黄醇激活核受体。 RA 刺激抑制了原发性人类心血管细胞钙化，而 RAR 抑制剂 AGN 193109 或 RARα siRNA 治疗则增加了钙化。 RA 以协调的方式减弱钙化，增加钙化抑制剂 MGP（基质 Gla 蛋白）的水平，同时降低促进钙化的 TNAP（组织非特异性碱性磷酸酶）活性。鉴于核受体作用随不同配体结构的变化而变化，我们比较了环状类视黄醇和非环状类视黄醇peretinoin的钙化反应。 Peretinoin 抑制人心血管细胞钙化，但不会诱导 APOC3（载脂蛋白-CIII）分泌，从而促进动脉粥样硬化形成，也不会减少 CYP7A1（细胞色素 P450 家族 7 亚家族 A 成员 1）的表达（循环维甲酸全反式 RA，9-顺式会出现这种情况） RA和13-顺式RA。此外，peretinoin 不抑制人股骨成骨细胞矿化，而全反式 RA 抑制成骨细胞矿化。 结论 这些结果建立了类维生素A对人类心血管钙化的调节，为参与这些反应的机制提供了新的见解，并表明选择性类维生素A调节剂，如无环类维生素A，可以治疗心血管钙化，而不会产生与环状类维生素A相关的副作用。