title: Nonmuscle myosin heavy chain and histone H3 are intracellular binding partners of lithospermic acid B and mediate its antiproliferative effect on VSMCs.
abstract: Lithospermic acid B (LAB), an active component of danshen, is known to inhibit the proliferation of vascular smooth muscle cells (VSMCs) and has pharmacological activity scavenging free radicals in VSMCs. However, the precise mechanism through which LAB exerts its antiproliferative effect is unclear. Therefore, we investigated how LAB regulates cellular proliferation in primary cultured rat VSMCs. Using fluorescein isothiocyanate (FITC)-conjugated LAB to track its cellular localization, we show that LAB localizes to the nucleus, specifically to the nucleolus, where it binds to histone H3, leading to the inhibition of the platelet-derived growth factor (PDGF)- induced phosphorylation of histone H3. LAB also only moves into the nucleus during the normal expression of nonmuscle myosin heavy chain (NMHC-IIA), which is associated with LAB in VSMCs. Notably, LAB suppressed the PDGF-induced phosphorylation of Akt and the expression of cyclin D2 in the presence of NMHC-IIA expression. Knockdown of NMHC-IIA expression impeded the function of LAB, which was then unable to inhibit the PDGF-induced proliferation of VSMCs. We conclude that LAB modulates the PDGF-induced proliferation of VSMCs by interacting with NMHC-IIA, which allows LAB to localize in the nucleus and to suppress the PDGF-induced proliferation of VSMCs.
authors.affiliation: Endocrinology, Brain Korea 21 Project for Medical Science, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Y H
authors.initials: YH
authors.lastname: Cho
authors.forename: E Y
authors.initials: EY
authors.lastname: Lim
authors.forename: J M
authors.initials: JM
authors.lastname: Kim
authors.forename: M
authors.initials: M
authors.lastname: Jung
authors.forename: H C
authors.initials: HC
authors.lastname: Lee
authors.forename: M
authors.initials: M
authors.lastname: Seo
authors.forename: E J
authors.initials: EJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D001572:Benzofurans / Q000378:metabolism* / Q000494:pharmacology*; D002466:Cell Nucleolus / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D056742:Cyclin D2 / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D053630:Depsides / Q000378:metabolism* / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006657:Histones / Q000378:metabolism*; D020409:Molecular Motor Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001572:Benzofurans; C486197:Ccnd2 protein, rat; D056742:Cyclin D2; D053630:Depsides; D006131:Growth Inhibitors; D006657:Histones; C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; C076944:salvianolic acid B; D051057:Proto-Oncogene Proteins c-akt; D018995:Myosin Heavy Chains