Ca2+ cycling and new therapeutic approaches for heart failure.
Ca2+ cycling and new therapeutic approaches for heart failure.
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DOI：
10.1161/circulationaha.109.890954
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发表时间：
2010-02-16
期刊：
影响因子：
37.8
通讯作者：
Marks AR
中科院分区：
文献类型：
--
作者：
Lompré AM;Hajjar RJ;Harding SE;Kranias EG;Lohse MJ;Marks AR
心力衰竭（HF）是西方国家的主要健康问题。尽管在药物和基于器械的治疗方面取得了重大进展，但所造成的疾病负担继续增加，特别是随着人口老龄化。65岁以后HF发病率接近10/1000。1充血性心力衰竭是多种心血管疾病的最终结果，包括动脉粥样硬化、心肌病和高血压。HF被描述为涉及循环系统、神经激素系统和肾系统相互作用的复杂病理生理综合征，HF首先是心肌疾病，尽管它很快引起其他系统的缺陷。目前针对HF的治疗集中于阻断神经激素通路，可改善生存率，但不能阻止HF的进展。晚期HF预后差，治疗选择有限。面对这些挑战，研究人员正在探索新的治疗方案。慢性HF与交感神经流出增加相关，这可能在早期是代偿性的，但长期神经激素激活诱导对心脏的显著损伤;此外，它导致β-肾上腺素能受体（β-AR）信号级联的多种改变，包括受体下调、受体激酶上调和抑制性G蛋白功能增加。2钙循环的幅度和速度是通过激酶和磷酸酶的磷酸化和去磷酸化的动态平衡来调节的。β-AR的激活刺激cAMP的产生，并导致兴奋-收缩偶联的关键调节因子如L-型Ca 2+通道、受磷蛋白、肌钙蛋白I、兰尼碱受体（RyR）、肌球蛋白结合蛋白C和蛋白磷酸酶抑制剂-1的蛋白激酶A（PKA）磷酸化（I-1;图），这导致Ca 2+循环的幅度和速度增加，并在逐搏基础上增加收缩性。3蛋白磷酸酶PP 1和PP 2A平衡这些蛋白的磷酸化。有明确的证据表明，肌浆网（SR）的Ca 2+循环的改变是衰竭心脏收缩性能受损的一个组成部分。4、5细胞内Ca ~（2+）处理异常包括SR Ca ~（2+）通过RyR渗漏，6 SR Ca ~（2+）摄取减少，7 SR含量减少。SR Ca 2+摄取受损是由于SR Ca 2+泵SERCA 2a（Sarco/内质网Ca 2 + ATP酶）7-9的较低表达和受磷蛋白的抑制功能增加所致。此外，Ca 2+通过激活各种激酶和磷酸酶，作用于Ca 2+依赖性转录途径。
Heart failure (HF) is a major health problem in Western countries. Despite significant progress in pharmacological and device-based treatment, the disease burden imposed continues to increase, particularly as the population ages. HF incidence approaches 10 per 1000 after age 65 years. 1 Congestive HF is the final consequence of diverse cardiovascular disorders, including atherosclerosis, cardiomyopathy, and hypertension. Described as a complex pathophysiological syndrome that involves interactions of the circulatory, neurohormonal, and renal systems, HF is first a disease of the myocardium, although it soon induces defects in other systems. Current treatments for HF, focused on blocking neurohormonal pathways, improve survival, but they do not halt the progression of HF. Late-stage HF has a poor prognosis, and therapeutic options are limited. Faced with these challenges, researchers are exploring novel therapeutic options. Chronic HF is associated with increased sympathetic outflow, which may be compensatory early on, but long-term neurohormonal activation induces significant damage to the heart; in addition, it results in multiple alterations in the ß-adrenergic receptor (ß-AR) signaling cascade, including receptor downregulation, upregulation of receptor kinases, and increased inhibitory G-protein function. 2 The amplitude and velocity of Ca2+ cycling are regulated by a dynamic balance of phosphorylation and dephosphorylation through kinases and phosphatases. Activation of ß-ARs stimulates cAMP production and results in protein kinase A (PKA) phosphorylation of key regulators of excitationcontraction coupling, such as L-type Ca2+ channels, phospholamban, troponin I, ryanodine receptors (RyR), myosinbinding protein C, and protein phosphatase inhibitor-1 (I-1; Figure), which leads to increased amplitude and velocity of Ca2+ cycling and increased contractility on a beat-to-beat basis. 3 Protein phosphatases PP1 and PP2A counterbalance phosphorylation of these proteins. There is clear evidence that alterations in sarcoplasmic reticulum (SR) Ca2+ cycling are a component of the impaired contractile performance of the failing heart. 4, 5 The abnormal intracellular Ca2+ handling includes SR Ca2+ leak through the RyR, 6 decreased SR Ca2+ uptake, 7 and decreased SR content. Impaired SR Ca2+ uptake results from lower expression of the SR Ca2+ pump, SERCA2a (Sarco/endoplasmic reticulum Ca2+ ATPase), 7–9 and from an increased inhibitory function of phospholamban. 10 Furthermore, Ca2+, via the activation of various kinases and phosphatases, acts on Ca2+-dependent transcription pathways.