Department of Surgery, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
Go Urabe
Department of Surgery, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; Department of Physiology & Cell Biology, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
Lynn Marcho
Department of Surgery, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; Department of Physiology & Cell Biology, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
Matthew Stratton
Department of Physiology & Cell Biology, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
Lian-Wang Guo
Department of Surgery, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; Department of Physiology & Cell Biology, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; Corresponding author
Craig K. Kent
Department of Surgery, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; Corresponding author
Summary: Vascular smooth muscle cell (VSMC) proliferation promotes intimal hyperplasia (IH) in occluding vascular diseases. Here we identified a positive role of ALDH1A3 (an aldehyde dehydrogenase) in this pro-IH process. The expression of ALDH1A3, but not that of 18 other isoforms of the ALDH family, was substantially increased in cytokine-stimulated VSMCs. PDGF(BB) stimulated VSMC total ALDH activity and proliferation, whereas ALDH1A3 silencing abolished this effect. ALDH1A3 silencing also diminished the expression of two matricellular proteins (TNC1 and ESM1), revealing a previously unrecognized ALDH1A3 function. Loss-of-function experiments demonstrated that TNC1 and ESM1 mediated ALDH1A3's pro-proliferative function via activation of AKT/mTOR and/or MEK/ERK pathways. Furthermore, ALDH inhibition with disulfiram blocked VSMC proliferation/migration in vitro and decreased TNC1 and ESM1 and IH in angioplasty-injured rat carotid arteries. Thus, ALDH1A3 promotes VSMC proliferation at least partially through TNC1/ESM1 upregulation; dampening excessive ALDH1A3 activity represents a potential approach to IH mitigation. : Pathophysiology; Vascular Remodeling; Molecular Biology; Molecular Mechanism of Behavior Subject Areas: Pathophysiology, Vascular Remodeling, Molecular Biology, Molecular Mechanism of Behavior
