Hoshijima Masahiko
University of California San Diego, Institute of Molecular Medicine, Department of Medicine, UCSD School of Medicine, UCSD0641, 9500 Gilman Dr., La Jolla, CA 92093, USA.
Pharmacol Ther. 2005 Mar;105(3):211-28. doi: 10.1016/j.pharmthera.2004.10.006. Epub 2005 Jan 8.
Chronic congestive heart failure primarily of ischemic origin remains a leading cause of morbidity and mortality in the United States and other leading countries. The current main stream of therapy is, however, palliative and uses a complex regimen of drugs, the actions of which are not understood completely. On the other hand, unfavorable remodeling after cardiac injuries of multiple causes has been thought to lead to cardiac contractile dysfunction in heart failure, and a body of scientific evidence points to a central role of intrinsic defects in intracellular calcium handling in cardiomyocytes that arise from the distorted functions of several key regulatory molecules on plasma membrane or sarcoplasmic reticulum (SR), a muscle-specific intracellular membrane complex that stores calcium at high concentration. Accordingly, the initial appetite to use gene transfer strategies to modulate calcium regulatory proteins was to validate molecular targets for the development of new pharmaceuticals; however, remarkable therapeutic efficacies found in an initial series of studies using various heart failure animal models immediately promoted us to seek ways to directly apply gene transfer to cure clinical heart failure. The first part of this article reviews our up-to-date knowledge of various functional components to regulate calcium handling in cardiomyocytes, including beta-adrenergic receptor, L-type calcium channel, ryanodine receptor (RyR) and its associated proteins, sarco-endoplasmic reticulum calcium ATPase (SERCA), and phospholamban (PLN), and their abnormalities in failing hearts. A series of new somatic gene transfer attempts targeting calcium handling in cardiomyocytes are discussed thereafter.
主要由缺血引起的慢性充血性心力衰竭仍是美国和其他主要国家发病和死亡的主要原因。然而，目前的主流治疗方法是姑息性的，使用复杂的药物方案，其作用尚未完全明了。另一方面，多种原因导致的心脏损伤后不利的重塑被认为会导致心力衰竭时心脏收缩功能障碍，大量科学证据表明，心肌细胞内钙处理的内在缺陷起核心作用，这些缺陷源于质膜或肌浆网（SR）上几种关键调节分子的功能失调，肌浆网是一种能高浓度储存钙的肌肉特异性细胞内膜复合体。因此，最初利用基因转移策略调节钙调节蛋白的目的是验证新药物开发的分子靶点；然而，在最初一系列使用各种心力衰竭动物模型的研究中发现的显著治疗效果立即促使我们寻求直接应用基因转移来治疗临床心力衰竭的方法。本文第一部分回顾了我们目前对调节心肌细胞钙处理的各种功能成分的认识，包括β-肾上腺素能受体、L型钙通道、兰尼碱受体（RyR）及其相关蛋白、肌浆网钙ATP酶（SERCA）和受磷蛋白（PLN），以及它们在衰竭心脏中的异常情况。此后讨论了一系列针对心肌细胞钙处理的新的体细胞基因转移尝试。
