Crosstalk between cardiomyocytes and noncardiomyocytes is essential to prevent cardiomyocyte apoptosis induced by proteasome inhibition.
Crosstalk between cardiomyocytes and noncardiomyocytes is essential to prevent cardiomyocyte apoptosis induced by proteasome inhibition.
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心肌细胞和非心肌细胞之间的串扰对于防止蛋白酶体抑制诱导的心肌细胞凋亡至关重要
DOI：
10.1038/s41419-020-03005-8
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发表时间：
2020-09-19
影响因子：
9
通讯作者：
He XB
中科院分区：
文献类型：
--
作者：
Guo F;Zhang CC;Yin XH;Li T;Fang CH;He XB
心脏是一个多细胞器官，由各种细胞类型相互作用组成。心肌细胞在不同的心脏应激反应中可能受益于或遭受与非心肌细胞的串扰。蛋白酶体功能障碍是一种常见的心脏应激反应，可引起心脏蛋白毒性，导致心力衰竭和心肌梗死等心脏疾病。心肌细胞和非心肌细胞之间的串扰在心脏蛋白毒性防御中的作用仍然未知。在这里，我们报告了在由心肌细胞和其他三种主要心肌细胞类型组成的异质培养物中，蛋白酶体抑制后心肌细胞特异性存活。相反，在由大多数心肌细胞组成的均质培养物中，蛋白酶体抑制显著诱导心肌细胞凋亡，证明了非心肌细胞在预防由蛋白酶体抑制引起的心肌细胞凋亡中不可或缺的作用。我们进一步表明，心肌细胞表达脑钠肽（BNP）作为细胞外分子在蛋白酶体抑制反应。阻断非心肌细胞上的BNP受体可显著加剧心肌细胞凋亡，表明心肌细胞释放的细胞外BNP在激活非心肌细胞的保护性反馈中具有旁分泌功能。最后，我们证明了蛋白酶体抑制激活的BNP在心肌细胞中的转录上调与阻遏元件1沉默转录因子（REST）/组蛋白去乙酰化酶1（HDAC 1）阻遏复合物从BNP基因启动子的解离有关。因此，HDAC抑制剂治疗可进一步增强BNP的诱导。我们的结论是，心肌细胞和非心肌细胞之间的串扰起着至关重要的作用，在保护心肌细胞免受蛋白毒性应激，并确定心肌细胞释放的BNP作为一种新的旁分泌信号分子介导这种串扰。这些发现为蛋白酶体功能障碍相关心脏疾病的关键调节因子和心脏保护机制提供了新的见解。
Heart is a multi-cellular organ made up of various cell types interacting with each other. Cardiomyocytes may benefit or suffer from crosstalk with noncardiomyocytes in response to diverse kinds of cardiac stresses. Proteasome dysfunction is a common cardiac stress which causes cardiac proteotoxicity and contributes to cardiac diseases such as heart failure and myocardial infarction. The role of crosstalk between cardiomyocytes and noncardiomyocytes in defense of cardiac proteotoxicity remains unknown. Here, we report a cardiomyocyte-specific survival upon proteasome inhibition in a heterogeneous culture consisting of cardiomyocytes and other three major cardiac cell types. Conversely, cardiomyocyte apoptosis is remarkably induced by proteasome inhibition in a homogeneous culture consisting of a majority of cardiomyocytes, demonstrating an indispensable role of noncardiomyocytes in the prevention of cardiomyocyte apoptosis resulting from proteasome inhibition. We further show that cardiomyocytes express brain natriuretic peptide (BNP) as an extracellular molecule in response to proteasome inhibition. Blockade of BNP receptor on noncardiomyocytes significantly exacerbated the cardiomyocyte apoptosis, indicating a paracrine function of cardiomyocyte-released extracellular BNP in activation of a protective feedback from noncardiomyocytes. Finally, we demonstrate that proteasome inhibition-activated transcriptional up-regulation of BNP in cardiomyocytes was associated with the dissociation of repressor element 1 silencing transcription factor (REST)/ histone deacetylase 1 (HDAC1) repressor complex from BNP gene promoter. Consistently, the induction of BNP could be further augmented by the treatment of HDAC inhibitors. We conclude that the crosstalk between cardiomyocytes and noncardiomyocytes plays a crucial role in the protection of cardiomyocytes from proteotoxicity stress, and identify cardiomyocyte-released BNP as a novel paracrine signaling molecule mediating this crosstalk. These findings provide new insights into the key regulators and cardioprotective mechanism in proteasome dysfunction-related cardiac diseases.
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DOI：
10.1007/s00018-017-2737-0
发表时间：
2018-04
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Man J;Barnett P;Christoffels VM
通讯作者：
Christoffels VM
影响因子：
4.8
作者：
Liang, QR;De Windt, LJ;Molkentin, JD
通讯作者：
Molkentin, JD
影响因子：
15.9
作者：
Li, Jie;Horak, Kathleen M.;Wang, Xuejun
通讯作者：
Wang, Xuejun
影响因子：
20.1
作者：
McLendon PM;Robbins J
通讯作者：
Robbins J
影响因子：
20.1
作者：
Haubner, Bernhard J.;Schneider, Johanna;Penninger, Josef M.
通讯作者：
Penninger, Josef M.