Mol Pharma：科学家揭示毛地黄可以抵御高血压和心力衰竭

近日，来自密歇根大学健康系统的研究者通过研究发现，一个使用了几个世纪的老药可以在机体的血管中激活一种机体保护机制。这种古老的心脏药物激发了中医的灵感，使得中医们使用这种药物来治疗处于瘟疫人群和过重人群。早在13世纪，有毒的草本植物毛地黄就被用于清理伤口，而且其干叶被用来酿酒以治疗因为心脏问题而导致的腿部肿胀。

这篇刊登在国际杂志Molecular Pharmacology上的研究文章中，研究者揭示了地高辛/毛地黄可以增强人体保护机制用以抵抗高血压和心力衰竭。减少盐摄入或者保持一个健康的体重可以预防高血压，但是在美国有1/3的人都患有高血压，这会给患者带来多方面的健康影响。当前的疗法就是通过阻止过度的荷尔蒙和压力信号，这些信号可以引发高血压和心力衰竭。但是最新的研究成果发现机体有能力产生一系列的RGS蛋白来进行机体自检。研究者通过寻找这种老的药物来重启高血压患者机体内缺失的这种抵御高血压的机制。

研究者Benita表示，我们检测了数千种抑制的药物和生物活性分子，这些药物都有增强RGS2和RGS4表达的潜力，研究者识别出了地高辛的一种新的机制。研究者发现毛地黄中含有很多地高辛，地高辛用于治疗充血性心力衰竭的病人。研究者揭示了低剂量的地高辛可以增加心脏和肾脏中RGS2的水平。而且地高辛新的生理作用可以帮助我们揭示低剂量药物可以增加心衰病人生存率的事实，这也证实了低剂量的地高辛可以起到一种保护性机制的作用。

编译自：New Action for Ancient Heart Drug

编译者：天使托

doi:10.1124/mol.112.079293
PMC:
PMID:

Cardiotonic Steroids Stabilize RGS2 Protein Levels

Benita Sjogren1, Sergio Parra1, Lauren J Heath1, Kevin B Atkins1, Zijian Xie2 and Richard Neubig1,*

Regulator of G protein signaling 2 (RGS2), a Gq-specific GTPase activator protein (GAP), is strongly implicated in cardiovascular function. RGS2-/- mice are hypertensive and prone to heart failure and several rare human mutations that speed RGS2 degradation have been identified in hypertensive patients. Consequently, pharmacological up-regulation of RGS2 protein levels could be beneficial. We utilized a β-galactosidase complementation method to screen several thousand compounds with known pharmacological function for those that increase RGS2 protein levels. Several cardiotonic steroids (CTS), including ouabain and digoxin increase RGS2 but not RGS4 protein levels. CTS increase RGS2 protein levels through a posttranscriptional mechanism by slowing protein degradation. RGS2 mRNA levels in primary vascular smooth muscle cells are unaffected by CTS treatment while protein levels are increased 2-3 fold. Na/K-ATPase is required for the increase in RGS2 protein levels as the effect is lost in Na/K-ATPase knock-down cells. Furthermore we demonstrate that CTS-induced increases in RGS2 are functional, reducing receptor-stimulated Gq-dependent ERK phosphorylation. Finally, we show that in vivo treatment with digoxin leads to increased RGS2 protein levels in heart and kidney. CTS-induced increases in RGS2 protein levels and function should modify several deleterious mechanisms in hypertension and heart failure. This novel CTS mechanism could contribute to the beneficial actions of low dose digoxin in heart failure. Additionally, our results support the concept of small-molecule modulation of RGS2 protein levels as a new strategy for cardiovascular therapeutics.