From the Faculty of Biology, Medicine and Health, The University of Manchester, United Kingdom (P.B., S.W., M.Z., L.C., S.K., Y.L., N.H., E.S., A.R., D.O., E.J.C., X.W., W.L.).
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA (M.R., J.C.).
Circ Res. 2019 Mar;124(5):696-711. doi: 10.1161/CIRCRESAHA.118.312829.
Secreted and membrane-bound proteins, which account for 1/3 of all proteins, play critical roles in heart health and disease. The endoplasmic reticulum (ER) is the site for synthesis, folding, and quality control of these proteins. Loss of ER homeostasis and function underlies the pathogenesis of many forms of heart disease.
To investigate mechanisms responsible for regulating cardiac ER function, and to explore therapeutic potentials of strengthening ER function to treat heart disease.
Screening a range of signaling molecules led to the discovery that Pak (p21-activated kinase)2 is a stress-responsive kinase localized in close proximity to the ER membrane in cardiomyocytes. We found that Pak2 cardiac deleted mice (Pak2-CKO) under tunicamycin stress or pressure overload manifested a defective ER response, cardiac dysfunction, and profound cell death. Small chemical chaperone tauroursodeoxycholic acid treatment of Pak2-CKO mice substantiated that Pak2 loss-induced cardiac damage is an ER-dependent pathology. Gene array analysis prompted a detailed mechanistic study, which revealed that Pak2 regulation of protective ER function was via the IRE (inositol-requiring enzyme)-1/XBP (X-box-binding protein)-1-dependent pathway. We further discovered that this regulation was conferred by Pak2 inhibition of PP2A (protein phosphatase 2A) activity. Moreover, IRE-1 activator, Quercetin, and adeno-associated virus serotype-9-delivered XBP-1s were able to relieve ER dysfunction in Pak2-CKO hearts. This provides functional evidence, which supports the mechanism underlying Pak2 regulation of IRE-1/XBP-1s signaling. Therapeutically, inducing Pak2 activation by genetic overexpression or adeno-associated virus serotype-9-based gene delivery was capable of strengthening ER function, improving cardiac performance, and diminishing apoptosis, thus protecting the heart from failure.
Our findings uncover a new cardioprotective mechanism, which promotes a protective ER stress response via the modulation of Pak2. This novel therapeutic strategy may present as a promising option for treating cardiac disease and heart failure.
分泌型和膜结合型蛋白占所有蛋白的 1/3，它们在心脏健康和疾病中发挥着关键作用。内质网（ER）是这些蛋白合成、折叠和质量控制的场所。ER 平衡和功能的丧失是许多形式心脏病发病的基础。
研究调节心脏 ER 功能的机制，并探索增强 ER 功能治疗心脏病的治疗潜力。
筛选一系列信号分子导致发现 Pak（p21 激活激酶）2 是一种应激反应性激酶，在心肌细胞中定位于 ER 膜附近。我们发现，在衣霉素应激或压力超负荷下，Pak2 心脏缺失小鼠（Pak2-CKO）表现出 ER 反应缺陷、心脏功能障碍和严重的细胞死亡。对 Pak2-CKO 小鼠进行小化学伴侣牛磺熊脱氧胆酸治疗证实，Pak2 缺失诱导的心脏损伤是一种依赖 ER 的病理学。基因芯片分析促使进行了详细的机制研究，该研究揭示了 Pak2 对保护性 ER 功能的调节是通过 IRE（肌醇需求酶）-1/XBP（X 盒结合蛋白）-1 依赖性途径进行的。我们进一步发现，这种调节是由 Pak2 抑制 PP2A（蛋白磷酸酶 2A）活性赋予的。此外，IRE-1 激活剂槲皮素和腺相关病毒血清型 9 递送的 XBP-1s 能够缓解 Pak2-CKO 心脏中的 ER 功能障碍。这提供了功能证据，支持了 Pak2 调节 IRE-1/XBP-1s 信号的机制。在治疗上，通过基因过表达或腺相关病毒血清型 9 为基础的基因传递诱导 Pak2 激活能够增强 ER 功能，改善心脏性能并减少细胞凋亡，从而保护心脏免受衰竭。
我们的发现揭示了一种新的心脏保护机制，通过调节 Pak2 促进保护性 ER 应激反应。这种新的治疗策略可能成为治疗心脏病和心力衰竭的有前途的选择。
