Mothers against decapentaplegic homolog 4 as a proteomic hub in vascular remodeling and residual cardiovascular risk

Abstract

Translational cardiovascular medicine increasingly relies on systems-level approaches to uncover therapeutic targets that bridge molecular mechanisms and clinical outcomes. Recent proteomic analyses in experimental myocardial infarction models highlight how modulation of multiple protein networks can confer cardioprotection, emphasizing the complexity of post-infarction remodeling. Among this systems framework, mothers against decapentaplegic homolog 4 (SMAD4) has emerged as a pivotal mediator of transforming growth factor-β/bone morphogenetic protein signaling, integrating hemodynamic forces with endothelial, smooth muscle, and extracellular matrix responses. Experimental evidence demonstrates that SMAD4 governs endothelial mechanotransduction, vascular smooth muscle cell phenotype, fibrosis, and inflammation, while its loss promotes vascular instability, arteriovenous malformations and pulmonary vascular remodeling. High-throughput proteomics highlights SMAD4 as a network hub regulating cytoskeletal organization, oxidative stress, and extracellular matrix dynamics, providing mechanistic insight into processes contributing to plaque vulnerability and residual cardiovascular risk. Although not yet validated as a circulating biomarker, SMAD4 expression in vascular and immune cells may complement established markers such as low-density lipoprotein cholesterol and high-sensitivity C-reactive protein when integrated within multi-marker proteomic and artificial intelligence-assisted risk models. Therapeutically, cell-specific SMAD4 modulation, RNA-based strategies, and targeted interference with upstream signaling represent promising avenues for precision cardiology.

Keywords: Atherothrombosis; Biomarkers; Endothelial dysfunction; Precision cardiology; Proteomics; Residual cardiovascular risk; Mothers against decapentaplegic homolog 4; Vascular smooth muscle cells

Core Tip: Proteomics is reshaping cardiovascular medicine by revealing network-level molecular mechanisms underlying myocardial infarction and atherothrombosis. Among emerging targets, mothers against decapentaplegic homolog 4 (SMAD4), a central mediator of transforming growth factor-β/bone morphogenetic protein signaling, has gained attention as an interesting regulator linking disturbed flow, inflammation, fibrosis, and vascular remodeling across endothelial and smooth muscle cells. Although not yet supported by large randomized trials, SMAD4 represents a proteomic network hub that may complement established biomarkers such as low-density lipoprotein cholesterol and high-sensitivity C-reactive protein. Integrated within multi-protein signatures and artificial intelligence-based models, SMAD4 may contribute to improved prediction of residual cardiovascular risk and precision phenotyping.