Identification of myocardial contractility-related genes as regenerative targets and diagnostic biomarkers in coronary artery disease.

Coronary artery disease (CAD) causes irreversible myocardial dysfunction and progressive heart failure due to loss of contractile function and limited endogenous regenerative capacity. Current therapeutic strategies fail to restore lost myocardium or regenerate damaged cardiac tissue. Identifying dysregulated contractility-related genes may reveal actionable targets for stem cell engineering, iPSC-derived cardiomyocyte design, and tissue regeneration aimed at restoring myocardial contractility and function. Transcriptomic data from the GSE20680 dataset (195 total samples; 87 CAD cases versus 52 healthy controls, N = 139; 56 intermediate stenosis subjects used for sensitivity analyses) were analyzed. Functional enrichment was performed with clusterProfiler, and protein-protein interaction (PPI) networks were constructed with STRING/Cytoscape. Protein validation was conducted in peripheral blood mononuclear cells (PBMCs) from 64 angiographically confirmed CAD patients and 55 matched healthy controls by Western blotting, with diagnostic accuracy assessed by receiver operating characteristic (ROC) analysis. Mechanistic studies employed human coronary artery smooth muscle cells (HCASMCs) transduced with lentiviral overexpression vectors or transfected with siRNA constructs targeting selected DEGs; proliferation (colony formation assay) and apoptosis (Annexin V/PI flow cytometry) were evaluated to establish regenerative targeting rationale. Differential expression analysis identified 319 DEGs (226 downregulated, 93 upregulated). Nine myocardial contractility-related genes were prioritized: UQCRQ, COX7C, COX6C, SLC8A1, COX7B, COX7A2, TNNT2, CACNB2, and CACNB1. Protein expression changes in PBMC lysates were directionally consistent with mRNA dysregulation: eight genes were significantly downregulated at the protein level, while COX7B was upregulated (P < 0.05). ROC analysis demonstrated robust diagnostic performance (AUC 0.799-0.900). In HCASMCs, correcting dysregulation of the eight downregulated genes (by lentiviral overexpression) suppressed proliferation and enhanced apoptosis, suggesting restoration of contractile phenotype. COX7B exhibited the reverse pattern, supporting its distinct detrimental role. These expression patterns suggest that gene correction in engineered cardiomyocytes could restore contractile function and improve cell survival post-transplantation. This nine-gene contractility-related signature represents a set of CAD-associated biomarkers with plausible links to myocardial excitation-contraction pathways. Our integrated PBMC and HCASMC data suggest that these genes may influence vascular remodeling, and they highlight candidate targets for future regenerative studies, but direct validation in human myocardial tissue and cardiomyocytes will be required before firm conclusions about myocardial contractility or regenerative efficacy can be drawn.