SWAP70 Promotes Atherosclerosis Via Endothelial CAV1 Nuclear Translocation

BACKGROUND: Atherosclerosis, the leading cause of coronary artery disease, is initiated and exacerbated by disturbed blood flow and chronic endothelial inflammation. SWAP70 (Switch-associated protein 70), a multifunctional signaling adaptor, has been genetically linked to coronary artery disease susceptibility via the risk allele rs10840293. However, its precise role in atherogenesis remains poorly understood. METHODS: We employed both endothelial cell-specific Swap70 overexpression and knockout mouse models, alongside lentiviral overexpression and siRNA-mediated SWAP70 knockdown in human umbilical vein endothelial cells, to investigate the functional role of SWAP70 in vascular inflammation and plaque development. In vitro assays subjected human umbilical vein endothelial cells to oscillatory shear stress or proinflammatory cytokines, followed by evaluation of adhesion molecule and chemokine expression. Mechanistic studies were performed using coimmunoprecipitation, proximity ligation assay, mimetic peptide interference, RNA sequencing, and ChIP-qPCR analyses. RESULTS: SWAP70 expression was significantly upregulated in human atherosclerotic plaques and in human umbilical vein endothelial cells exposed to oscillatory shear stress compared with laminar shear stress. On oscillatory shear stress stimulation, SWAP70 bound to the scaffolding domain of CAV1 (caveolin-1) to facilitate its nuclear translocation, thereby enhancing transcription of key inflammatory mediators, including adhesion molecules and chemokines. In vitro, SWAP70 knockdown suppressed oscillatory shear stress and TNF-α (tumor necrosis factor-α)-induced proinflammatory gene expression. In vivo, endothelial-specific deletion of Swap70 attenuated high-fat diet-induced atherosclerotic lesion formation, reduced vascular inflammation, and improved plaque stability. Conversely, overexpression of Swap70 amplified inflammatory responses and worsened atherogenic outcomes. CONCLUSIONS: Our findings identify SWAP70 as a mechano-responsive regulator of endothelial inflammation and atherosclerosis, acting through a novel mechanism involving CAV1 nuclear translocation. Targeting the SWAP70-CAV1 signaling axis represents a promising therapeutic strategy for mitigating vascular inflammation and attenuating the progression of atherosclerotic cardiovascular disease.