title: Piperlongumine inhibits atherosclerotic plaque formation and vascular smooth muscle cell proliferation by suppressing PDGF receptor signaling.
abstract: Piperlongumine (piplartine, PL) is an alkaloid found in the long pepper (Piper longum L.) and has well-documented anti-platelet aggregation, anti-inflammatory, and anti-cancer properties; however, the role of PL in prevention of atherosclerosis is unknown. We evaluated the anti-atherosclerotic potential of PL in an in vivo murine model of accelerated atherosclerosis and defined its mechanism of action in aortic vascular smooth muscle cells (VSMCs) in vitro. Local treatment with PL significantly reduced atherosclerotic plaque formation as well as proliferation and nuclear factor-kappa B (NF-κB) activation in an in vivo setting. PL treatment in VSMCs in vitro showed inhibition of migration and platelet-derived growth factor BB (PDGF-BB)-induced proliferation to the in vivo findings. We further identified that PL inhibited PDGF-BB-induced PDGF receptor beta activation and suppressed downstream signaling molecules such as phospholipase Cγ1, extracellular signal-regulated kinases 1 and 2 and Akt. Lastly, PL significantly attenuated activation of NF-κB-a downstream transcriptional regulator in PDGF receptor signaling, in response to PDGF-BB stimulation. In conclusion, our findings demonstrate a novel, therapeutic mechanism by which PL suppresses atherosclerosis plaque formation in vivo.
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA.
authors.forename: Dong Ju
authors.initials: DJ
authors.lastname: Son
authors.forename: Soo Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Seong Su
authors.initials: SS
authors.lastname: Han
authors.forename: Chan Woo
authors.initials: CW
authors.lastname: Kim
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kumar
authors.forename: Byeoung Soo
authors.initials: BS
authors.lastname: Park
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Lee
authors.forename: Yeo Pyo
authors.initials: YP
authors.lastname: Yun
authors.forename: Hanjoong
authors.initials: H
authors.lastname: Jo
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Park
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D002339:Carotid Arteries; D049109:Cell Proliferation / Q000187:drug effects; D004148:Dioxolanes / Q000008:administration & dosage*; D004195:Disease Models, Animal; D008026:Ligation; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D058226:Plaque, Atherosclerotic / Q000517:prevention & control*; D017479:Receptors, Platelet-Derived Growth Factor / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction; D010881:Piperidones
chemical_list: D001057:Apolipoproteins E; D004148:Dioxolanes; D016328:NF-kappa B; D017479:Receptors, Platelet-Derived Growth Factor; C498077:piperlongumine; D010881:Piperidones