Clinical role and mechanism of miR-4443 in coronary heart disease: a prognostic marker and regulator of vascular smooth muscle cell Function

BACKGROUND: Dysregulation of vascular smooth muscle cell (VSMC) function is a key factor in coronary heart disease (CHD) pathogenesis. This study investigates the role of miR-4443 in regulating VSMC behavior and its potential as a clinical biomarker. METHODS: Clinical data from 200 CHD patients were retrospectively analyzed. miR-4443 expression levels were quantified via RT-qPCR in paired plasma specimens and in VSMC exposed to oxidized low-density lipoprotein (ox-LDL). Prognostic relevance was evaluated through Kaplan-Meier analysis and multivariate Cox regression modeling. Cellular transfection, CCK-8, Transwell, and dual-luciferase reporter assays were employed to evaluate VSMC proliferation, migration, and gene regulatory mechanisms. RESULTS: CHD patients exhibited significantly higher serum levels of miR‑4443 relative to healthy controls. Univariate analysis revealed significant associations between the risk of major adverse cardiovascular events (MACEs) and miR‑4443, BMI, LDL‑C, and CRP. After multivariable adjustment, elevated miR‑4443 expression retained independent prognostic value for adverse outcomes (HR = 2.812, 95% CI: 1.130-6.997, P = 0.026). Kaplan-Meier analysis revealed an elevated cumulative incidence of MACEs in patients exhibiting high miR-4443 levels relative to those with low expression. In ox-LDL-induced VSMCs, miR-4443 expression was upregulated. Functionally, miR-4443 promoted VSMC proliferation and migration, while its inhibition suppressed these processes. TIMP2 expression was reduced in CHD patients. Furthermore, luciferase reporter assays confirmed TIMP2 as a direct target of miR-4443, through which miR-4443 regulates VSMC function. CONCLUSION: miR-4443 functions as a prognostic biomarker in CHD by targeting TIMP2 to regulate VSMC proliferation and migration, highlighting its dual diagnostic and therapeutic potential.