Pharmacological inhibition of βIIPKC is cardioprotective in late-stage hypertrophy.
Pharmacological inhibition of βIIPKC is cardioprotective in late-stage hypertrophy.
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DOI：
10.1016/j.yjmcc.2011.08.025
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发表时间：
2011-12
影响因子：
5
通讯作者：
Mochly-Rosen D
中科院分区：
文献类型：
--
作者：
Ferreira JC;Koyanagi T;Palaniyandi SS;Fajardo G;Churchill EN;Budas G;Disatnik MH;Bernstein D;Brum PC;Mochly-Rosen D
我们先前发现，在高血压Dahl盐敏感大鼠的心脏中，βIIPKC水平在从代偿性心肌肥厚到心功能不全的转变过程中增加。在这里，我们发现，使用βIIPKC特异性抑制剂βIIV5-3对这些高血压大鼠进行为期6周的治疗，可将它们的生存时间延长至少6周，抑制心肌纤维化和炎症，并推迟从代偿性肥厚到心功能障碍的转变。此外，在βIIPKC治疗的大鼠中，未观察到βIIPKC治疗的高血压大鼠的钙处理蛋白SERCA2和钠/钙交换蛋白以及肌钙蛋白I磷酸化水平的变化，这表明IIPKC参与了心肌钙水平的调节。相反，选择性的βIPKC抑制剂，βIPKC的另一种剪接形式，在这些大鼠中没有任何益处。我们还发现，βIIV5-3，而不是βIV5-3，改善了分离的大鼠心肌细胞的钙离子处理，并增强了分离的大鼠心脏的收缩能力。总之，我们使用心脏功能障碍(晚期肥厚)的活体模型的数据表明，βIIPKC参与了与心力衰竭相关的病理，因此βIIPKC的抑制剂可能是这种疾病的潜在治疗方法。
We previously found that in the hearts of hypertensive Dahl salt-sensitive rats, βIIPKC levels increase during the transition from compensated cardiac hypertrophy to cardiac dysfunction. Here we showed that a six-week treatment of these hypertensive rats with a βIIPKC-specific inhibitor, βIIV5-3, prolonged their survival by at least six weeks, suppressed myocardial fibrosis and inflammation, and delayed the transition from compensated hypertrophy to cardiac dysfunction. In addition, changes in the levels of the Ca2+-handling proteins, SERCA2 and the Na+/Ca2+ exchanger, as well as troponin I phosphorylation, seen in the control-treated hypertensive rats were not observed in the βIIPKC-treated rats, suggesting that βIIPKC contributes to the regulation of calcium levels in the myocardium. In contrast, treatment with the selective inhibitor of βIPKC, an alternative spliced form of βIIPKC, had no beneficial effects in these rats. We also found that βIIV5-3, but not βIV5-3, improved calcium handling in isolated rat cardiomyocytes and enhanced contractility in isolated rat hearts. In conclusion, our data using an in vivo model of cardiac dysfunction (late-phase hypertrophy), suggest that βIIPKC contributes to the pathology associated with heart failure and thus an inhibitor of βIIPKC may be a potential treatment for this disease.
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影响因子：
6.1
作者：
Ferreira, Julio C. B.;Moreira, Jose B. N.;Brum, Patricia C.
通讯作者：
Brum, Patricia C.
影响因子：
37.8
作者：
Iwanga, Y;Kihara, Y;Sasayama, S
通讯作者：
Sasayama, S
影响因子：
7.7
作者：
Arikawa, Emi;Ma, Ronald C. W.;King, George L.
通讯作者：
King, George L.
影响因子：
15.9
作者：
Qi, Xin;Inagaki, Koichi;Mochly-Rosen, Daria
通讯作者：
Mochly-Rosen, Daria
DOI：
10.1152/ajpheart.2001.280.5.h2264
发表时间：
2001-05-01
影响因子：
4.8
作者：
Roman, BB;Geenen, DL;Buttrick, PM
通讯作者：
Buttrick, PM