miR-195-3p alleviates atherosclerosis by regulating VSMC functions through JNK2/NF-κB pathway

Background and Aim: Atherosclerosis is a chronic inflammatory vascular disease and the primary pathological driver of life-threatening cardiovascular diseases. Vascular smooth muscle cells (VSMCs) contribute critically to vascular remodeling; their aberrant proliferation, migration, phenotypic switching and inflammatory activation promote atherosclerotic lesion development. miR-195-3p is a potential vasculo-protective microRNA, yet its exact functions and downstream mechanisms in VSMC-related atherosclerosis remain poorly defined. This study investigated the biological role of miR-195-3p in VSMCs and its molecular regulatory axis. Methods and Results miR-195-3p expression was measured in plasma from patients with coronary artery disease, atherosclerotic aortas from high-fat diet-fed ApoE⁻/⁻ mice, and pathologically stimulated VSMCs. miR-195-3p was significantly downregulated under atherosclerotic conditions. Gain- and loss-of-function assays showed that miR-195-3p overexpression suppressed VSMC proliferation, migration and inflammation while preserving the contractile phenotype, whereas miR-195-3p inhibition induced pathological VSMC dysfunction. Transcriptomic, bioinformatic and dual-luciferase assays identified JNK2 as a direct target of miR-195-3p. Rescue experiments confirmed JNK2 mediates miR-195-3p’s protective effects, and JNK2 aggravates VSMC dysfunction partly through activating the NF-κB inflammatory cascade. In ApoE⁻/⁻ mice, AAV-mediated miR-195-3p overexpression reduced plaque burden, repressed JNK2/NF-κB signaling, restored VSMC homeostasis and mitigated vascular inflammation. Conclusions miR-195-3p maintains VSMC homeostasis and alleviates atherosclerosis by directly targeting JNK2 and inhibiting the NF-κB cascade. The miR-195-3p/JNK2/NF-κB axis enriches our understanding of atherosclerosis pathogenesis and offers candidate molecular targets for atherosclerotic cardiovascular disease therapy.