Reduced blood EPAC1 protein levels as a marker of severe coronary artery disease: the role of hypoxic foam cell-transformed smooth muscle cells.

BACKGROUND: Vascular smooth muscle cells loaded with cholesterol (foam-VSMCs) play a crucial role in the progression of human atherosclerosis. Exchange Protein Directly Activated by cAMP 1 (EPAC1) is a critical protein in the regulation of vascular tone, endothelial function, and inflammation. Our objectives were to identify proteins specifically secreted by foam human coronary VSMCs (foam-hcVSMC) to evaluate their potential as circulating biomarkers for diagnosing coronary artery disease (CAD), and to ascertain the mechanisms underlying their levels in the blood of patients with CAD. METHODS AND RESULTS: Differential proteomics identified EPAC1 as a differential foam-hcVSMC-secreted protein. Circulating EPAC1 levels were measured by ELISA in blood from 202 patients with suspected CAD who underwent coronary computed tomography angiography (CCTA). Blood EPAC1 levels were significantly lower in CAD patients compared to controls (p < 0.001). EPAC1 levels were reduced in both men and women with severe CAD (SIS > 4) compared to those with moderate CAD (SIS 1-4). ROC analysis identified 9.16 ng/ml as the optimal EPAC1 cut-off for severe CAD. At this threshold, EPAC1 predicted severe CAD (SIS > 4) with 69.6% sensitivity and 79.4% specificity, outperforming hs-CRP and hs-TnT in predicting CAD severity. Real-time PCR and Western blot analysis revealed that human foam-SMCs under hypoxic conditions exhibited a significant reduction in EPAC1 mRNA (p = 0.013) and protein (p < 0.001) levels. CONCLUSIONS: These findings suggest that circulating EPAC1 protein levels lower than 9.16 ng/mL are predictive of severe CAD in humans. Hypoxic foam-SMCs, characteristic of advanced atherosclerotic lesions, exhibit diminished production of EPAC1, potentially contributing to the decreased circulating EPAC1 levels in patients with severe CAD.