Inflammation-Related Factors S100A9 and TLR2 in Cardiomyocyte Hypertrophy.

Abstract

Objective: The pathogenesis and progression of heart failure (HF) are governed by complex, interconnected biological pathways, with dysregulated immune responses and maladaptive cardiac remodeling playing central roles. Although specific inflammatory mediators have been implicated in modulating critical features of cardiac remodeling-such as cardiomyocyte hypertrophy and extracellular matrix fibrosis-the precise molecular mechanisms driving these processes remain incompletely characterized.

Methods: Integrated bioinformatics analysis of HF and hypertrophic cardiomyopathy (HCM) transcriptomic datasets identified pathologically relevant candidate genes. A protein-protein interaction (PPI) network was constructed from these candidates using the STRING database, followed by module analysis. Serum S100 calcium-binding protein A9 (S100A9) protein expression in HF patients was quantified by Western blotting under reducing conditions. The functional relevance of prioritized genes was subsequently validated through: (i) in vitro cyclic mechanical stretch in primary neonatal rat cardiomyocytes, and (ii) in vivo pressure overload modeling via transverse aortic constriction (TAC) in mice.

Results: Bioinformatics analysis of HF and HCM datasets revealed a significant association between immune function and cardiac remodeling. Using CytoNCA, we identified core genes, among which the top 25 included multiple inflammatory pathway-related factors, such as S100A9 and Toll-like receptor 2 (TLR2). Notably, S100A9 levels were significantly elevated in the serum of HF patients and in mechanically stretched cardiomyocytes. This increase correlated with upregulated expression of hypertrophy-related markers, including atrial natriuretic peptide (ANP). Furthermore, mechanical stretch-induced S100A9 upregulation markedly enhanced TLR2 expression in cardiomyocytes. Importantly, TLR2 inhibition substantially attenuated the mechanical stretch-induced upregulation of S100A9 mRNA expression, as well as the subsequent hypertrophic and inflammatory responses in cardiomyocytes.

Conclusion: The inflammatory mediators S100A9 and TLR2 engage in reciprocal activation that amplifies the hypertrophic response in mechanically stretched cardiomyocytes. This pathogenic cross-talk exacerbates maladaptive remodeling and likely accelerates HF progression.