Roles of heat shock protein A12A in the development of diabetic cardiomyopathy

IF 3.3 3区 生物学 Q3 CELL BIOLOGY
Yunxiao Jia , Yunhao Yu , Chenxi Gao , Yuehua Li , Chuanfu Li , Zhengnian Ding , Qiuyue Kong , Li Liu
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引用次数: 0

Abstract

Long-term hyperglycemia can lead to diabetic cardiomyopathy (DCM), a main lethal complication of diabetes. However, the mechanisms underlying DCM development have not been fully elucidated. Heat shock protein A12A (HSPA12A) is the atypic member of the Heat shock 70kDa protein family. In the present study, we found that the expression of HSPA12A was upregulated in the hearts of mice with streptozotocin-induced diabetes, while ablation of HSPA12A improved cardiac systolic and diastolic dysfunction and increased cumulative survival of diabetic mice. An increased expression of HSPA12A was also found in H9c2 cardiac cells following treatment with high glucose (HG), while overexpression of HSPA12A-enhanced the HG-induced cardiac cell death, as reflected by higher levels of propidium iodide cells, lactate dehydrogenase leakage, and caspase 3 cleavage. Moreover, the HG-induced increase of oxidative stress, as indicated by dihydroethidium staining, was exaggerated by HSPA12A overexpression. Further studies demonstrated that the HG-induced increases of protein kinase B and forkhead box transcription factors 1 phosphorylation were diminished by HSPA12A overexpression, while pharmacologically inhibition of protein kinase B further enhanced the HG-induced lactate dehydrogenase leakage in HSPA12A overexpressed cardiac cells. Together, the results suggest that hyperglycemia upregulated HSPA12A expression in cardiac cells, by which induced cell death to promote DCM development. Targeting HSPA12A may serve as a potential approach for DCM management.

热休克蛋白 A12A 在糖尿病心肌病发病过程中的作用
长期高血糖可导致糖尿病心肌病(DCM),这是糖尿病的一种主要致命并发症。然而,DCM 的发病机制尚未完全阐明。热休克蛋白 A12A(HSPA12A)是 HSP70 家族的非典型成员。在本研究中,我们发现 HSPA12A 在链脲佐菌素(STZ)诱导的糖尿病小鼠心脏中表达上调,而消融 HSPA12A 可改善糖尿病小鼠的心脏收缩和舒张功能障碍,并提高其累积存活率。高糖(HG)处理后,H9c2 心脏细胞中 HSPA12A 的表达也增加了,而 HSPA12A 的过表达增强了 HG 诱导的心脏细胞死亡,这反映在更高水平的碘化丙啶(PI+)细胞、乳酸脱氢酶(LDH)渗漏和 caspase 3 裂解上。此外,HSPA12A 的过表达还加剧了 HG 诱导的氧化应激的增加,二氢乙锭(DHE)染色表明了这一点。进一步的研究表明,HG 诱导的 Akt 和叉头框转录因子 1(FOXO1)磷酸化的增加会因 HSPA12A 的过表达而减弱,而药物抑制蛋白激酶 B(Akt)会进一步增强 HG 诱导的 HSPA12A 过表达心脏细胞的 LDH 泄漏。这些结果表明,高血糖会上调心脏细胞中 HSPA12A 的表达,从而诱导细胞死亡,促进 DCM 的发展。以 HSPA12A 为靶点可能是治疗 DCM 的一种潜在方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Stress & Chaperones
Cell Stress & Chaperones 生物-细胞生物学
CiteScore
7.60
自引率
2.60%
发文量
59
审稿时长
6-12 weeks
期刊介绍: Cell Stress and Chaperones is an integrative journal that bridges the gap between laboratory model systems and natural populations. The journal captures the eclectic spirit of the cellular stress response field in a single, concentrated source of current information. Major emphasis is placed on the effects of climate change on individual species in the natural environment and their capacity to adapt. This emphasis expands our focus on stress biology and medicine by linking climate change effects to research on cellular stress responses of animals, micro-organisms and plants.
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