Altered cardiac innate immunity is highly associated with the progression of cardiac disease states and heart failure. S100A8/A9 is an important component of damage-associated molecular patterns (DAMPs) that is critically involved in the pathogenesis of heart failure, thus considered a promising target for pharmacological intervention. In the current study, initially, we validated the role of S100A8/A9 in contributing to cardiac injury and heart failure via the overactivation of the β-adrenergic pathway and tested the potential use of paquinimod as a pharmacological intervention of S100A8/A9 activation in preventing cardiac dysfunction, collagen deposition, inflammation, and immune cell infiltration in β-adrenergic overactivation–mediated heart failure. This finding was further confirmed by the cardiomyocyte-specific silencing of S100A9 via the use of the adeno-associated virus (AAV) 9-mediated short hairpin RNA (shRNA) gene silencing system. Most importantly, in the assessment of the underlying cellular mechanism by which activated S100A8/A9 cause aggravated progression of cardiac fibrosis and heart failure, we discovered that the activated S100A8/A9 can promote fibroblast-macrophage interaction, independent of inflammation, which is likely a key mechanism leading to the enhanced collagen production. Our results revealed that targeting S100A9 provides dual beneficial effects, which is not only a strategy to counteract cardiac inflammation but also preclude cardiac fibroblast-macrophage interactions. The findings of this study also indicate that targeting S100A9 could be a promising strategy for addressing cardiac fibrosis, potentially leading to future drug development.

心脏先天免疫的改变与心脏病状态和心力衰竭的进展密切相关。S100A8/A9 是损伤相关分子模式 (DAMP) 的重要组成部分，与心力衰竭的发病机制密切相关，因此被认为是药物干预的有希望的目标。在当前的研究中，我们首先验证了 S100A8/A9 通过过度激活 β-肾上腺素能通路在导致心脏损伤和心力衰竭中的作用，并测试了帕喹莫德作为 S100A8/A9 激活的药理学干预在预防心力衰竭方面的潜在用途。 β-肾上腺素能过度激活介导的心力衰竭中的心脏功能障碍、胶原沉积、炎症和免疫细胞浸润。通过使用腺相关病毒 (AAV) 9 介导的短发夹 RNA (shRNA) 基因沉默系统对 S100A9 进行心肌细胞特异性沉默，进一步证实了这一发现。最重要的是，在评估激活的 S100A8/A9 导致心脏纤维化和心力衰竭恶化的潜在细胞机制时，我们发现激活的 S100A8/A9 可以促进成纤维细胞-巨噬细胞相互作用，而与炎症无关，这可能是导致胶原蛋白产生增强的关键机制。我们的结果显示，靶向 S100A9 具有双重有益作用，这不仅是对抗心脏炎症的策略，而且还可以防止心脏成纤维细胞-巨噬细胞相互作用。这项研究的结果还表明，针对 S100A9 可能是解决心脏纤维化的一种有前景的策略，有可能促进未来的药物开发。