# Cyclodextrin Counteracts Coxsackievirus-Induced Cardiac Damage by Protecting Desmosome Integrity and Suppressing Proinflammatory Cytokine Expression

## TL;DR

Cyclodextrin helps protect the heart from coxsackievirus damage by preserving desmosomes and reducing inflammation.

## Contribution

Cyclodextrin is shown to upregulate NFAT5, protect desmosomes, and suppress proinflammatory cytokines in CVB3-induced myocarditis.

## Key findings

- Cyclodextrin upregulates NFAT5 and restores desmoplakin expression in cardiomyocytes.
- Cyclodextrin inhibits CVB3 replication and reduces proinflammatory cytokine levels.
- NFAT5 is critical for desmosomal integrity and directly regulates desmoplakin expression.

## Abstract

Nuclear factor of activated T cells 5 (NFAT5), an osmosensitive transcription factor, has been shown to protect against coxsackievirus B3 (CVB3)-induced myocarditis but is susceptible to cleavage by viral proteases. Identifying agents that upregulate NFAT5 may offer a novel antiviral strategy. Cyclodextrins, cyclic oligosaccharides that influence cellular osmolality, are promising candidates. In this study, we demonstrate that NFAT5 is critical for maintaining desmosomal integrity in cardiomyocytes. Cardiac-specific Nfat5-knockout mice showed a significant reduction in desmosomes, as observed by transmission electron microscopy. Furthermore, we identified desmoplakin (DSP), a structural desmosomal protein, as a direct transcriptional target of NFAT5, with reduced expression in Nfat5-knockout mouse hearts and NFAT5-knockdown HeLa cells. Notably, treatment with 5 mM cyclodextrin significantly upregulated NFAT5 expression with minimal cytotoxicity, restored DSP expression, and suppressed CVB3 replication by inhibiting viral RNA transcription, protein synthesis, and virion production. Additionally, cyclodextrin reduced mRNA levels of proinflammatory cytokines interleukin-1 beta and interleukin-8, indicating its potential role as an alleviator of excessive cytokine production. These findings identify NFAT5 as a key regulator of desmoplakin expression and prove cyclodextrin as a dual-functioning agent in counteracting cardiac damage through NFAT5-DSP-mediated protection of desmosome integrity and suppressing proinflammatory cytokine expression in CVB3-induced myocarditis.