HSPA12A acts as a scaffolding protein to inhibit cardiac fibroblast activation and cardiac fibrosis.
HSPA12A acts as a scaffolding protein to inhibit cardiac fibroblast activation and cardiac fibrosis.
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HSPA12A作为支架蛋白抑制心脏成纤维细胞活化和心脏纤维化。
DOI：
10.1016/j.jare.2024.01.012
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发表时间：
2024-01
影响因子：
10.7
通讯作者：
Qian Mao;Xiaojin Zhang;Jinna Yang;Qiuyue Kong;Hao Cheng;Wansu Yu;Xiaofei Cao;Yuehua Li;Chuanfu Li;Li Liu;Zhengnian Ding
中科院分区：
文献类型：
--
作者：
Qian Mao;Xiaojin Zhang;Jinna Yang;Qiuyue Kong;Hao Cheng;Wansu Yu;Xiaofei Cao;Yuehua Li;Chuanfu Li;Li Liu;Zhengnian Ding
心脏纤维化是几乎所有类型的心脏疾病（包括心肌梗死（MI））中不良重构和进行性功能下降的主要驱动因素。心脏成纤维细胞（CF）活化为肌成纤维细胞是导致心脏纤维化的原因。不幸的是，没有理想的方法来控制CF activationcurrently existing.ObjectivesThis研究探讨热休克蛋白A12 A（HSPA 12 A），热休克蛋白70家族的非典型成员，在CF激活和MI诱导的心脏fibrosis.MethodsPrimary CF和HSPA 12 a基因敲除小鼠的作用。CF激活通过肌成纤维细胞特征（包括α-平滑肌肌动蛋白（αSMA）、胶原蛋白和纤连蛋白）的上调来指示。Masson三色染色和天狼星苦红染色显示心肌纤维化。采用超声心动图检查心脏功能。糖酵解活性通过细胞外乳酸水平和相关蛋白表达来指示。在放线菌酮和MG 132处理后检查蛋白质稳定性。结果HSPA 12 A在静息状态CF中表达增强，而在活化状态CF中表达减弱;消融HSPA 12 A可促进CF的活化和心肌纤维化。HSPA 12 A过表达通过抑制糖酵解抑制初级CF的活化，而HSPA 12 A敲低则表现出相反的作用。此外，HSPA 12 A上调转录因子p53的蛋白表达，从而介导了HSPA 12 A诱导的糖酵解抑制和CF激活。从机制上讲，HSPA 12 A的这种作用是通过作为一种支架蛋白结合p53和泛素特异性蛋白酶10（USP 10），从而促进USP 10介导的p53蛋白的稳定性和p53介导的糖酵解inhibition.ConclusionThe本研究提供了明确的证据表明，HSPA 12 A是一种新的内源性抑制CF激活和心脏纤维化。靶向CF中的HSPA 12 A可能代表了治疗患者心脏纤维化的有希望的策略。
IntroductionCardiac fibrosis is the main driver for adverse remodeling and progressive functional decline in nearly all types of heart disease including myocardial infarction (MI). The activation of cardiac fibroblasts (CF) into myofibroblasts is responsible for cardiac fibrosis. Unfortunately, no ideal approach for controlling CF activation currently exists.ObjectivesThis study investigated the role of Heat shock protein A12A (HSPA12A), an atypical member of the HSP70 family, in CF activation and MI-induced cardiac fibrosis.MethodsPrimary CF andHspa12aknockout mice were used in the experiments. CF activation was indicated by the upregulation of myofibroblast characters including alpha-Smooth muscle actin (αSMA), Collagen, and Fibronectin. Cardiac fibrosis was illustrated by Masson’s trichrome and picrosirius staining. Cardiac function was examined using echocardiography. Glycolytic activity was indicated by levels of extracellular lactate and the related protein expression. Protein stability was examined following cycloheximide and MG132 treatment. Protein-protein interaction was examined by immunoprecipitation-immunoblotting analysis.ResultsHSPA12A displayed a high expression level in quiescent CF but showed a decreased expression in activated CF, while ablation of HSPA12A in mice promoted CF activation and cardiac fibrosis following MI. HSPA12A overexpression inhibited the activation of primary CF through inhibiting glycolysis, while HSPA12A knockdown showed the opposite effects. Moreover, HSPA12A upregulated the protein expression of transcription factor p53, by which mediated the HSPA12A-induced inhibition of glycolysis and CF activation. Mechanistically, this action of HSPA12A was achieved by acting as a scaffolding protein to bind p53 and ubiquitin specific protease 10 (USP10), thereby promoting the USP10-mediated p53 protein stability and the p53-medicated glycolysis inhibition.ConclusionThe present study provided clear evidence that HSPA12A is a novel endogenous inhibitor of CF activation and cardiac fibrosis. Targeting HSPA12A in CF could represent a promising strategy for the management of cardiac fibrosis in patients.