Glembotski Christopher C
SDSU Heart Institute and the Department of Biology, San Diego State University, 5500 Campanile Dr, San Diego, CA 92182, USA.
Circ Res. 2007 Nov 9;101(10):975-84. doi: 10.1161/CIRCRESAHA.107.161273.
Over the last decade, it has become clear that the accumulation of misfolded proteins contributes to a number of neurodegenerative, immune, and endocrine pathologies, as well as other age-related illnesses. Recent interest has focused on the possibility that the accumulation of misfolded proteins can also contribute to vascular and cardiac diseases. In large part, the misfolding of proteins takes place during synthesis on free ribosomes in the cytoplasm or on endoplasmic reticulum ribosomes. In fact, even under optimal conditions, approximately 30% of all newly synthesized proteins are rapidly degraded, most likely because of improper folding. Accordingly, stresses that perturb the folding of proteins during or soon after synthesis can lead to the accumulation of misfolded proteins and to potential cellular dysfunction and pathological consequences. To avert such outcomes, cells have developed elaborate protein quality-control systems for detecting misfolded proteins and making appropriate adjustments to the machinery responsible for protein synthesis and/or degradation. Important contributors to protein quality control include cytosolic and organelle-targeted molecular chaperones, which help fold and stabilize proteins from unfolding, and the ubiquitin proteasome system, which degrades terminally misfolded proteins. Both of these systems play important roles in cardiovascular biology. The focus of this review is the endoplasmic reticulum stress response, a protein quality-control and signal-transduction system that has not been well studied in the context of cardiovascular biology but that could be important for vascular and cardiac health and disease.
在过去十年中，已明确错误折叠蛋白的积累会导致多种神经退行性、免疫和内分泌疾病，以及其他与年龄相关的病症。最近的研究兴趣集中在错误折叠蛋白的积累也可能导致血管和心脏疾病这一可能性上。很大程度上，蛋白质的错误折叠发生在细胞质中的游离核糖体或内质网核糖体上的合成过程中。事实上，即使在最佳条件下，所有新合成蛋白质中约30%会迅速降解，最可能的原因是折叠不当。因此，在蛋白质合成期间或之后不久干扰其折叠的应激会导致错误折叠蛋白的积累，并可能导致细胞功能障碍和病理后果。为避免此类结果，细胞已发展出复杂的蛋白质质量控制系统，用于检测错误折叠蛋白，并对负责蛋白质合成和/或降解的机制进行适当调整。蛋白质质量控制的重要贡献者包括靶向细胞质和细胞器的分子伴侣，它们有助于蛋白质折叠并防止其展开，以及泛素蛋白酶体系统，该系统可降解最终错误折叠的蛋白质。这两个系统在心血管生物学中都发挥着重要作用。本综述的重点是内质网应激反应，这是一种蛋白质质量控制和信号转导系统，在心血管生物学背景下尚未得到充分研究，但可能对血管和心脏健康及疾病很重要。
