1. Academic Validation
  2. Targeting S100A9 Prevents β-Adrenergic Activation-Induced Cardiac Injury

Targeting S100A9 Prevents β-Adrenergic Activation-Induced Cardiac Injury

  • Inflammation. 2024 Mar 6. doi: 10.1007/s10753-023-01944-w.
Jie Liu 1 Xin Chen 1 Lijun Zeng 1 Laiping Zhang 1 Fangjie Wang 2 Cuiping Peng 1 Xiaoyong Huang 3 Shuhui Li 4 Ying Liu 5 Weinian Shou 6 Xiaohui Li 7 Dayan Cao 8
Affiliations

Affiliations

  • 1 Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Army Medical University, Chongqing, 400038, People's Republic of China.
  • 2 State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.
  • 3 Institute of Immunology, PLA, Army Medical University, Chongqing, China.
  • 4 Department of Clinical Biochemistry, College of Pharmacy, Army Medical University, Chongqing, China.
  • 5 Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, USA.
  • 6 Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, USA. wshou@iu.edu.
  • 7 Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Army Medical University, Chongqing, 400038, People's Republic of China. lpsh008@aliyun.com.
  • 8 Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Army Medical University, Chongqing, 400038, People's Republic of China. dayancao@outlook.com.
Abstract

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.

Keywords

Cardiac fibrosis; Fibroblasts; Macrophages; Paquinimod; S100A9; β-adrenergic activation.

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