Division of Basic Biomedical Sciences and Cardiovascular Research Institute, Sanford School of Medicine of the University of South Dakota Vermillion, SD 57069, USA.
Am J Transl Res. 2010 Jul 21;2(4):390-401.
Molecular chaperones represent the first line of defense of intracellular protein quality control. As a major constituent of molecular chaperones, heat shock proteins (HSP) are known to confer cardiomyocyte short-term protection against various insults and injuries. Previously, we reported that the small HSP alphaB-crystallin (CryAB) attenuates cardiac hypertrophic response in mice subjected to 2 weeks of severe pressure overload. However, the long-term role of small HSPs in cardiac hypertrophy and failure has rarely been studied. The present study investigates the cardiac responses to chronic severe pressure overload in CryAB/HSPB2 germ line ablated (KO) and cardiac-specific CryAB overexpressingtransgenic (TG) mice. Pressure overload was induced by transverse aortic constriction in KO, TG, and non-transgenic wild type (NTG) control mice and 10 weeks later molecular, cellular, and whole organ level hypertrophic responses were analyzed. As we previously described, CryAB/HSPB2 KO mice showed abnormal baseline cardiac physiology that worsened into a restrictive cardiomyopathic phenotype with aging. Severe pressure overload in these mice led to rapid deterioration of heart function and development of congestive cardiac failure. Contrary to their short term protective phenotype, CryAB TG mice showed no significant effects on cardiac hypertrophic responses and very modest improvement of hemodynamics during chronic systolic overload. These findings indicate that small HSPs CryAB and/or HSPB2 are essential to maintain cardiac structure and function but overex-pression of CryAB is not sufficient to confer a sustained protection against chronic systolic overload.
分子伴侣是细胞内蛋白质质量控制的第一道防线。热休克蛋白（HSP）作为分子伴侣的主要组成部分，已知可赋予心肌细胞短期保护作用，以抵抗各种刺激和损伤。此前，我们报道了小分子 HSPαB-晶体蛋白（CryAB）可减轻 2 周严重压力超负荷小鼠的心肌肥厚反应。然而，小分子 HSP 在心肌肥厚和衰竭中的长期作用很少被研究。本研究探讨了 CryAB/HSPB2 基因敲除（KO）和心脏特异性 CryAB 过表达转基因（TG）小鼠在慢性严重压力超负荷下的心脏反应。通过横主动脉缩窄在 KO、TG 和非转基因野生型（NTG）对照小鼠中诱导压力超负荷，10 周后分析分子、细胞和全器官水平的肥厚反应。正如我们之前所描述的，CryAB/HSPB2 KO 小鼠表现出异常的基础心脏生理学，随着年龄的增长，这种生理学恶化成限制性心肌病表型。在这些小鼠中，严重的压力超负荷导致心脏功能迅速恶化，并发展为充血性心力衰竭。与它们的短期保护表型相反，CryAB TG 小鼠对心脏肥厚反应没有显著影响，在慢性收缩性超负荷期间对血液动力学的改善也非常轻微。这些发现表明，小分子 HSPs CryAB 和/或 HSPB2 对于维持心脏结构和功能是必不可少的，但 CryAB 的过表达不足以赋予对慢性收缩性超负荷的持续保护。
