Short-term S100A8/A9 Blockade Promotes Cardiac Neovascularization after Myocardial Infarction

J Cardiovasc Transl Res. 2024 Dec;17(6):1389-1399. doi: 10.1007/s12265-024-10542-6. Epub 2024 Jul 15.

Abstract

Acute-phase inhibition of the pro-inflammatory alarmin S100A8/A9 improves cardiac function post-myocardial infarction (MI), but the mechanisms underlying the long-term benefits of this short-term treatment remain to be elucidated. Here, we assessed the effects of S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 on myocardial neovascularization in mice with induced MI. The treatment significantly reduced S100A9 and increased neovascularization in the myocardium, assessed by CD31 staining. Proteomic analysis by mass-spectrometry showed strong myocardial upregulation of the pro-angiogenic proteins filamin A (~ 10-fold) and reticulon 4 (~ 5-fold), and downregulation of the anti-angiogenic proteins Ras homolog gene family member A (RhoA, ~ 4.7-fold), neutrophilic granule protein (Ngp, ~ 4.0-fold), and cathelicidin antimicrobial peptide (Camp, ~ 4.4-fold) versus controls. In-vitro, ABR-238901 protected against apoptosis induced by recombinant human S100A8/A9 in human umbilical vein endothelial cells (HUVECs). In conclusion, S100A8/A9 blockade promotes post-MI myocardial neovascularization by favorably modulating pro-angiogenic proteins in the myocardium and by inhibiting endothelial cell apoptosis.

Keywords: Inflammation; Myocardial infarction; Neovascularization; S100A8/A9.

MeSH terms

  • Angiogenesis Inducing Agents / pharmacology
  • Angiogenic Proteins / metabolism
  • Animals
  • Apoptosis* / drug effects
  • Calgranulin A* / genetics
  • Calgranulin A* / metabolism
  • Calgranulin B* / metabolism
  • Cells, Cultured
  • Coronary Vessels / drug effects
  • Coronary Vessels / metabolism
  • Disease Models, Animal*
  • Human Umbilical Vein Endothelial Cells* / drug effects
  • Human Umbilical Vein Endothelial Cells* / metabolism
  • Humans
  • Male
  • Mice, Inbred C57BL*
  • Myocardial Infarction* / drug therapy
  • Myocardial Infarction* / metabolism
  • Myocardial Infarction* / pathology
  • Neovascularization, Physiologic* / drug effects
  • Proteomics*
  • Signal Transduction
  • Time Factors

Substances

  • Calgranulin B
  • Calgranulin A
  • S100A9 protein, mouse
  • S100a8 protein, mouse
  • S100A9 protein, human
  • S100A8 protein, human
  • Angiogenic Proteins
  • Angiogenesis Inducing Agents