Salvianolic Acid a Disrupts the HSP90α-AKT-PERK Ternary Complex to Alleviate Atherosclerosis by Activating Endoplasmic Reticulum Stress of Senescent Vascular Smooth Muscle Cells.

Atherosclerosis is a chronic inflammatory disease driven by senescent vascular smooth muscle cells (VSMCs). Salvianolic acid A (SAA) exhibits cardiovascular protective effects; however, its role in atherosclerosis remains unclear. This study aimed to investigate the effects and targets of SAA in atherosclerosis. In vitro studies were performed in senescent VSMCs with heat shock protein 90 alpha (HSP90α) overexpression or knockdown, with or without SAA treatment. In vivo, ApoE-/- mice fed a high-fat diet were treated with SAA and adeno-associated virus-mediated VSMC-specific HSP90α overexpression or knockdown. SAA promoted apoptosis in senescent VSMCs by inhibiting HSP90α. This inhibition promoted ubiquitin-proteasome-dependent degradation of protein kinase B (AKT) and activation of PRKR-Like Endoplasmic Reticulum Kinase (PERK) signaling. SAA increased endoplasmic reticulum-mitochondrial contacts and mitochondrial calcium uptake. These effects were reversed by HSP90α overexpression. In ApoE-/- mice, SAA reduced the burden of senescent VSMCs, decreased the size of plaque, and increased the stability of the fibrous cap. VSMC-specific HSP90α knockdown mimicked the protective effects of SAA, whereas HSP90α overexpression reversed SAA-mediated effects on disease. SAA reduces the burden of senescent VSMCs in atherosclerosis by inhibiting the scaffold function of HSP90α which maintains the AKT-PERK interaction, to reactivate PERK signaling, thereby alleviating disease progression.