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.

心脏是一个多细胞器官，由相互相互作用的各种细胞类型组成。心肌细胞可能受益或遭受与非心肌细胞的串扰，以响应各种心脏压力。蛋白酶体功能障碍是一种常见的心脏应激，会导致心脏蛋白毒性并导致心脏疾病，如心力衰竭和心肌梗塞。心肌细胞和非心肌细胞之间的串扰在防御心脏蛋白毒性方面的作用仍然未知。在这里，我们报告了在由心肌细胞和其他三种主要心脏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，蛋白酶体抑制显着诱导心肌细胞凋亡，证明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发挥不可或缺的作用。我们进一步表明，心肌细胞表达脑钠肽（BNP）作为响应蛋白酶体抑制的细胞外分子。非心肌细胞上 BNP 受体的阻断显着加剧了心肌细胞凋亡，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，我们证明蛋白酶体抑制激活的 BNP 在心肌细胞中的转录上调与抑制因子 1 沉默转录因子 (REST)/组蛋白去乙酰化酶 1 (HDAC1) 抑制复合物从 BNP 基因启动子的解离有关。一贯地，通过治疗 HDAC 抑制剂可以进一步增强 BNP 的诱导。我们得出结论，心肌细胞和非心肌细胞之间的串扰在保护心肌细胞免受蛋白毒性应激方面起着至关重要的作用，并将心肌细胞释放的 BNP 鉴定为介导这种串扰的新型旁分泌信号分子。这些发现为蛋白酶体功能障碍相关心脏病的关键调节因子和心脏保护机制提供了新的见解。