2. Academic Validation
  3. 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.
PMID: 38446361 DOI: 10.1007/s10753-023-01944-w
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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