PP2Acα Deficiency in Vascular Smooth Muscle Cells Accelerates Aortic Aneurysm and Dissection by Regulating KLF4 Phosphorylation and Ubiquitination

Abstract Aortic aneurysm and dissection (AAD) are life‐threatening cardiovascular diseases with limited effective medical treatments. Protein phosphatase 2A (PP2A), the most abundant serine/threonine phosphatase in eukaryotes, is pivotal in regulating intracellular signaling. This study investigates the role of PP2A in the pathogenesis of AAD. Analysis of available datasets revealed that PP2Acα is the most significantly downregulated PP2A subunit in human and mouse aneurysm tissues. Vascular smooth muscle cell (VSMC)‐specific PP2Acα knockout exacerbates β‐Aminopropionitrile (BAPN)‐induced aortic dissection and elastase‐induced abdominal aortic aneurysm in mice. Collagen‐based contraction assays, Western blot, and gelatin zymography confirmed that the deficiency of PP2Acα results in decreased contractility, contractile markers, and elevated production of matrix metallopeptidase 2 (MMP2) in VSMCs. Furthermore, PP2Acα deficiency promoted VSMC phenotypic switching through stabilizing Kruppel‐like factor 4 (KLF4). Mechanistically, PP2Acα binds to and dephosphorylates protein kinase B 1 (AKT1), thereby reducing phosphorylation of the AKT1 substrate KLF4 at Thr398. The deficiency of PP2Acα diminishes KLF4 phosphorylation‐dependent ubiquitination and degradation, leading to the suppression of VSMC contractile gene transcription. The findings underscore a critical role for PP2Acα in regulating VSMC phenotypic switching and AAD progression by controlling KLF4 phosphorylation and ubiquitination, offering novel insights into the molecular pathogenesis underlying AAD.