Inhibition of S100A9 Improves Aortic Dissection in Association With Mitochondrial Function Enhancement.

Abstract

Background: Aortic dissection (AD) is a high-mortality cardiovascular emergency with unclear pathophysiological mechanisms. This study investigated S100 calcium-binding protein A9 (S100A9) as a therapeutic target for AD and explored its underlying mechanisms.

Methods: Proteomic analysis compared aortic tissues from patients with acute type A and matched non-dissected vascular tissues from the same patients. An AD model was induced in wild-type and S100A9 knockout mice via β-aminopropionitrile (BAPN). Survival, aortic diameter, and S100A9 expression were quantified. Furthermore, single-cell RNA sequencing was used to analyze cell populations and mitochondrial pathways in AD mice treated with an S100A9 inhibitor. Finally, the effect of S100A9 on mitochondrial function was investigated in Tohoku Hospital Pediatrics-1 (THP-1) cells.

Results: Proteomics identified that S100A9 is significantly upregulated in AD tissue. Furthermore, S100a9 knockout (S100a9 KO) mice conferred protection against AD-induced mortality and aortic dilation. Single-cell RNA analysis revealed that S100A9 is predominantly expressed within the granulocyte population. S100A9 inhibition activated mitochondrial oxidative phosphorylation pathways and upregulated mtDNA-encoded gene expression. Human tissue mRNA levels confirmed decreased mtDNA in AD. Moreover, recombinant human S100A9 and angiotensin-II treatment in THP-1 cells reduced mitochondrial membrane potential and increased oxidative stress.

Conclusions: S100A9 is a potential contributor to AD pathogenesis. Inhibition of S100A9 might be a promising therapeutic target for AD.