Resumption of intracellular Ca2+ cycling as a novel therapeutic strategy for heart failure

细胞内钙离子转运的改变在心力衰竭的病理生理学中起着关键作用。衰竭心肌细胞的一个典型特征是肌浆网(SR)内钙负荷能力的降低，这导致瞬时钙的幅度降低和衰减率减慢，舒张期[Ca^&lt；2+&gt；]_i增加。这种未加载的肌浆网钙离子减少可归因于肌浆网钙再摄取的减少，2+&gt；ATPase(SERCA)的增加Na~(++)/Ca~(2+)~(2+)交换(NCX)的过度表达和FK506结合蛋白从SR Ca~(2+)释放通道中解离，导致SR Ca~(2+)&gt；漏出增加。在临床研究中，包括洋地黄和β受体激动剂在内的许多变力药物都未能改善心力衰竭的长期预后。对于肌浆网钙离子的摄取，以cAMP非依赖的方式增加肌浆网钙离子摄取的药物是候选药物，包括蛋白磷酸酶抑制剂和MCC-135。2005年，我们对…进行了初步调查更重要的是，SERCA直接激动剂MCC-135对大鼠心肌细胞钙瞬变和细胞收缩的影响。遗憾的是，我们无法获得MCC-135的显著变力作用。2006年，我们研究了一种特异性蛋白磷酸酶-1抑制剂I-1对通透性大鼠心室肌细胞钙离子转运的影响。结果表明，I-1在不改变SR Ca~(2+)释放方式的情况下，增加了SR Ca~(2+)的含量。对于NCX，我们利用膜片钳技术阐明了NCX、SEA0400和SN-6等新型特异性抑制剂对豚鼠心肌细胞的抑制作用。SN-6选择性地抑制NCX的Ca~(2+)内流模式，SEA0400同样阻断Ca~(2+)外流和内流模式。SEA0400还通过保护高能量代谢来保护大鼠灌流心脏免受缺血/再灌注损伤。尽管临床使用有局限性，但这些药物的联合使用可能会恢复细胞内钙循环，并以较低的毒性改善心功能。较少

Altered cellular Ca^<2+> handling plays a key role in the pathophysiology of heart failure. A typical aspect of failing heart cells is a decrease in the ability to load Ca^<2+> in the sarcoplasmic reticulum (SR), which results in a decreased amplitude and a slowed decay rate of Ca^<2+> transients, and an increased diastolic [Ca^<2+>]_i. This unloaded SR Ca^<2+> could be ascribed to a decrease in Ca^<2+> re-uptake by SR Ca^<2+> ATPase (SERCA), an increase in Ca^<2+> extrusion by the over-expression of Na^+/Ca^<2+> exchange (NCX), and an increase in the SR Ca^<2+> leak by the dissociation of FK506-binding proteins from the SR Ca^<2+> release channel. Many inotropic agents including digitalis and β-receptor agonists have failed to improve long-term prognosis of heart failure in clinical studies. For the SR Ca2+ uptake, drugs that enhance SR Ca^<2+> uptake in a cAMP-independent manner, including protein phosphatase inhibitors and MCC-135, are candidates. In 2005, we initially investigated … More the effect of a direct SERCA activator, MCC-135, on the profiles of Ca^<2+> transients and cell contraction in isolated rat cardiomyocytes. Unfortunately, we could not obtain significant inotropic effects of MCC-135. In 2006, we studied the effect of I-1, a specific protein phosphatase-1 inhibitor on cellular Ca^<2+> handling in permeabilized rat ventricular myocytes. As a result, I-1 increased SR Ca^<2+> content without altering SR Ca^<2+> release manner. For NCX, we clarified the inhibition modality of novel specific inhibitors of NCX, SEA0400 and SN-6 using patch clamp technique in guinea pig ventricular myocytes. SN-6 inhibited Ca^<2+> influx mode of NCX selectively, and SEA0400 equally blocked both Ca^<2+> efflux and influx mode. SEA0400 also protected rat perfused hearts against ischemia/reperfusion injury by preserving high energy metabolism. Despite limitations for clinical use, the combination of these agents may restore cellular Ca^<2+> cycling and improve cardiac function with less toxicity. Less