Islam Moydul, Diwan Abhinav, Mani Kartik
Division of Cardiology, Washington University School of Medicine, St. Louis, MO, United States.
Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO, United States.
Front Physiol. 2020 Jun 4;11:586. doi: 10.3389/fphys.2020.00586. eCollection 2020.
Homeostasis in vertebrate systems is contingent on normal cardiac function. This, in turn, depends on intricate protein-based cellular machinery, both for contractile function, as well as, durability of cardiac myocytes. The cardiac small heat shock protein (csHsp) chaperone system, highlighted by αB-crystallin (CRYAB), a small heat shock protein (sHsp) that forms ∼3-5% of total cardiac mass, plays critical roles in maintaining proteostatic function via formation of self-assembled multimeric chaperones. In this work, we review these ancient proteins, from the evolutionarily preserved role of homologs in protists, fungi and invertebrate systems, as well as, the role of sHsps and chaperones in maintaining cardiac myocyte structure and function. We propose the concept of the "sarcostat" as a protein quality control mechanism in the sarcomere. The roles of the proteasomal and lysosomal proteostatic network, as well as, the roles of the aggresome, self-assembling protein complexes and protein aggregation are discussed in the context of cardiac myocyte homeostasis. Finally, we will review the potential for targeting the csHsp system as a novel therapeutic approach to prevent and treat cardiomyopathy and heart failure.
脊椎动物系统中的内稳态取决于正常的心脏功能。而这又依赖于复杂的基于蛋白质的细胞机制，这一机制对于心肌细胞的收缩功能以及耐久性都至关重要。心脏小热休克蛋白（csHsp）伴侣系统以αB-晶状体蛋白（CRYAB）为突出代表，αB-晶状体蛋白是一种小热休克蛋白（sHsp），占心脏总质量的约3-5%，通过形成自组装多聚体伴侣在维持蛋白质稳态功能中发挥关键作用。在这项工作中，我们回顾这些古老的蛋白质，从它们在原生生物、真菌和无脊椎动物系统中同源物的进化保守作用，以及sHsp和伴侣蛋白在维持心肌细胞结构和功能方面的作用。我们提出“肌节稳态蛋白”的概念，将其作为肌节中的一种蛋白质质量控制机制。在心肌细胞内稳态的背景下，讨论了蛋白酶体和溶酶体蛋白质稳态网络的作用，以及聚集体、自组装蛋白复合物和蛋白质聚集的作用。最后，我们将回顾靶向csHsp系统作为预防和治疗心肌病及心力衰竭的一种新型治疗方法的潜力。
