Targeting canonical TGFβ/SMAD3 and ERK1/2 signaling in human valve interstitial cells to modulate immune-fibrotic responses in rheumatic heart disease
Abstract
Rheumatic heart disease (RHD) is a chronic sequel of acute rheumatic fever characterized by sustained inflammation, fibrosis, and valve degeneration; however, the underlying processes remain unclear. To identify dysregulated molecular pathways, we conducted LC-MS/MS-based proteomic profiling of RHD mitral valve tissue compared with ischemic controls and validated systemic inflammation in RHD patients through peripheral blood analysis. Proteomic analysis revealed upregulation of immune response proteins, TGFβ signaling, and extracellular matrix (ECM) regulators. Notably, proteins associated with innate immune activation and macrophage-related pro- and anti-inflammatory responses were found to be enriched. Peripheral blood analysis further confirmed elevated levels of IL6, TNFα, and TIMP1, indicating systemic inflammation. To investigate the underlying mechanisms, we isolated human valve interstitial cells (hVICs) and treated them with proinflammatory stimuli (TNFα, IFNγ) and profibrotic/ anti-inflammatory (TGFβ) stimulation. TGFβ induced morphological changes within 24 h, consistent with fibrotic transformation, and upregulated fibrotic markers (ACTA2, COL1A1, COL1A2, TIMP1, CTGF, MMP2, and TGFβ) along with increased collagen deposition. In contrast, TNFα and IFNγ suppressed fibrotic gene expression while upregulating TIMP1. Notably, TGFβ induced canonical Smad3 phosphorylation, whereas TNFα and IFNγ did not find, any change. Further, macrophage-hVIC interactions were…
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