Crosstalk between cardiomyocytes and noncardiomyocytes is essential to prevent cardiomyocyte apoptosis induced by proteasome inhibition

Abstract

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.

Communication Between Cardiomyocytes and Fibroblasts During Cardiac Ischemia/Reperfusion and Remodeling: Roles of TGF-β, CTGF, the Renin Angiotensin Axis, and Non-coding RNA Molecules

“…This finding suggests a crucial protective role for non-CM cells, such as CF, in order to promote CM survival after proteasome inhibition. Moreover, this study found that brain natriuretic peptide is released from CM upon proteasome inhibition, signaling other cardiac cells to prevent proteasome inhibitioninduced CM death via a paracrine function (Guo et al, 2020). The mechanisms responsible for this crosstalk between CM and other cardiac cells, such as CF, remain to be elucidated.…”

Lidocaine Induces Apoptosis in Head and Neck Squamous Cell Carcinoma Through Activation of Bitter Taste Receptor T2R14

“…Lidocaine may inhibit the UPS by binding to the b5 subunit of the 20s proteasome in p53-postive cancer cells [148]. In any case, UPS inhibition can be linked to apoptosis [149][150][151][152]. Drugs that inhibit the catalytic activity of the UPS, including hallmark drugs like bortezomib and ixazomib [153] are used as chemotherapeutics as cancer cells have high rates of proteinturnover for survival [154].…”

Starvation Induces Diverse Autophagic Response in Cardiomyocytes and Noncardiomyocytes

“…Three cell culture containing different composition of cardiac cell types were performed as previously described [5]. Briefly, after decapitation, the ventricles of postnatal day 1 mouse pups were quickly dissected under a microscope.…”

“…To determine the kinetics of starvation-induced autophagy in different cardiac cell types in vitro, we recruited a previously well-defined primary heterogeneous cell culture composed of four major cardiac cell types, including SAA+ cardiomyocytes, DDR2+ cardiac fibroblasts, SMA+ vascular smooth muscle cells and Lectin+ endothelial cells [5]. Autophagic activity was quantified by the number of LC3 puncta in each cell expressing corresponding cell type markers.…”

“…To enable a parallel comparison without cross contamination, the heterogenous cell culture was optimized to generate a homogeneous cardiomyocyte culture and a noncardiomyocyte culture by previously established methods in our lab (Fig. 3A) [5].…”