Dhalla Naranjan S, Dent Melissa R, Tappia Paramjit S, Sethi Rajat, Barta Judit, Goyal Ramesh K
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, and Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
J Cardiovasc Pharmacol Ther. 2006 Mar;11(1):31-45. doi: 10.1177/107424840601100103.
It is now well known that congestive heart failure (CHF) is invariably associated with cardiac hypertrophy, and changes in the shape and size of cardiomyocytes (cardiac remodeling) are considered to explain cardiac dysfunction in CHF. However, the mechanisms responsible for the transition of cardiac hypertrophy to heart failure are poorly understood. Several lines of evidence both from various experimental models of CHF and from patients with different types of CHF have indicated that the functions of different subcellular organelles such as extracellular matrix, sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, and nucleus are defective. Subcellular abnormalities for protein contents, gene expression, and enzyme activities in the failing heart become evident as a consequence of prolonged hormonal imbalance, metabolic derangements, and cation maldistribution. In particular, the occurrence of oxidative stress, development of intracellular Ca2+ overload, activation of proteases and phospholipases, and alterations in cardiac gene expression result in changes in the biochemical composition, molecular structure, and function of different subcellular organelles (subcellular remodeling). Not only does subcellular remodeling appear to be intimately involved in the transition of cardiac hypertrophy to heart failure, the mismatching of the function of different subcellular organelles leads to the development of cardiac dysfunction. Although blockade of the renin-angiotensin system, sympathetic nervous system, and various other hormonal actions have been reported to produce beneficial effects on cardiac remodeling and heart dysfunction in CHF, the actions of various cardiac drugs on subcellular remodeling have not been examined extensively. Some recent studies have indicated that both the angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists attenuate changes in sarcolemma, sarcoplasmic reticulum, and myofibril enzyme activities, protein contents, and gene expression, and partly improve cardiac function in the failing hearts. It is suggested that subcellular remodeling is an excellent target for the development of improved drug therapy for CHF. Furthermore, extensive studies should investigate the effects of different agents individually or in combination on reverse subcellular remodeling, cardiac remodeling, and cardiac dysfunction in various experimental models of CHF.
现在众所周知，充血性心力衰竭（CHF）总是与心脏肥大相关，心肌细胞形状和大小的改变（心脏重塑）被认为可以解释CHF中的心脏功能障碍。然而，心脏肥大向心力衰竭转变的机制却知之甚少。来自各种CHF实验模型和不同类型CHF患者的几条证据表明，不同亚细胞器如细胞外基质、肌膜、肌浆网、肌原纤维、线粒体和细胞核的功能存在缺陷。由于长期的激素失衡、代谢紊乱和阳离子分布不均，衰竭心脏中蛋白质含量、基因表达和酶活性的亚细胞异常变得明显。特别是，氧化应激的发生、细胞内Ca2+过载的发展、蛋白酶和磷脂酶的激活以及心脏基因表达的改变导致不同亚细胞器的生化组成、分子结构和功能发生变化（亚细胞重塑）。亚细胞重塑似乎不仅与心脏肥大向心力衰竭的转变密切相关，不同亚细胞器功能的不匹配还导致心脏功能障碍的发展。尽管据报道阻断肾素-血管紧张素系统、交感神经系统和各种其他激素作用对CHF中的心脏重塑和心脏功能障碍有有益影响，但各种心脏药物对亚细胞重塑的作用尚未得到广泛研究。最近的一些研究表明，血管紧张素转换酶抑制剂和血管紧张素受体拮抗剂都能减弱肌膜、肌浆网和肌原纤维酶活性、蛋白质含量和基因表达的变化，并部分改善衰竭心脏的心脏功能。有人认为亚细胞重塑是开发改善CHF药物治疗的一个极佳靶点。此外，广泛的研究应调查不同药物单独或联合使用对各种CHF实验模型中逆向亚细胞重塑、心脏重塑和心脏功能障碍的影响。
