title: Dihydroaustrasulfone alcohol inhibits PDGF-induced proliferation and migration of human aortic smooth muscle cells through inhibition of the cell cycle.
abstract: Dihydroaustrasulfone alcohol is the synthetic precursor of austrasulfone, which is a marine natural product, isolated from the Taiwanese soft coral Cladiella australis. Dihydroaustrasulfone alcohol has anti-inflammatory, neuroprotective, antitumor and anti-atherogenic properties. Although dihydroaustrasulfone alcohol has been shown to inhibit neointima formation, its effect on human vascular smooth muscle cells (VSMCs) has not been elucidated. We examined the effects and the mechanisms of action of dihydroaustrasulfone alcohol on proliferation, migration and phenotypic modulation of human aortic smooth muscle cells (HASMCs). Dihydroaustrasulfone alcohol significantly inhibited proliferation, DNA synthesis and migration of HASMCs, without inducing cell death. Dihydroaustrasulfone alcohol also inhibited platelet-derived growth factor (PDGF)-induced expression of cyclin-dependent kinases (CDK) 2, CDK4, cyclin D1 and cyclin E. In addition, dihydroaustrasulfone alcohol inhibited PDGF-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), whereas it had no effect on the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/(Akt). Moreover, treatment with PD98059, a highly selective ERK inhibitor, blocked PDGF-induced upregulation of cyclin D1 and cyclin E and downregulation of p27kip1. Furthermore, dihydroaustrasulfone alcohol also inhibits VSMC synthetic phenotype formation induced by PDGF. For in vivo studies, dihydroaustrasulfone alcohol decreased smooth muscle cell proliferation in a rat model of restenosis induced by balloon injury. Immunohistochemical staining showed that dihydroaustrasulfone alcohol noticeably decreased the expression of proliferating cell nuclear antigen (PCNA) and altered VSMC phenotype from a synthetic to contractile state. Our findings provide important insights into the mechanisms underlying the vasoprotective actions of dihydroaustrasulfone alcohol and suggest that it may be a useful therapeutic agent for the treatment of vascular occlusive disease.
authors.affiliation: Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Lienhai Road, Kaohsiung 804, Taiwan. bme02@ndmctsgh.edu.tw.|Department of Biomedical Engineering, National Defense Medical Center, Sec. 6, Minquan E. Road, Taipei 11490, Taiwan. bme02@ndmctsgh.edu.tw.
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Lienhai Road, Kaohsiung 804, Taiwan. wzh@mail.nsysu.edu.tw.|Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung 80424, Taiwan. wzh@mail.nsysu.edu.tw.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Wen
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 250 Wuxing Street, Taipei 11042, Taiwan. edward0730@gmail.com.
authors.forename: Yen-Hsien
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Physiology and Biophysics; Graduate Institute of Physiology, National Defense Medical Center, Sec. 6, Minquan E. Road, Taipei 11490, Taiwan. helenaprey@gmail.com.
authors.forename: Chu-Lun
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung 80424, Taiwan. hanchun25@gmail.com.
authors.forename: Han-Chun
authors.initials: HC
authors.lastname: Hung
authors.affiliation: Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung 80424, Taiwan. anubis0620@gmail.com.
authors.forename: Chun-Hong
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan. ma4949@cgmh.org.tw.
authors.forename: Wu-Fu
authors.initials: WF
authors.lastname: Chen
authors.affiliation: Department of Physiology and Biophysics; Graduate Institute of Physiology, National Defense Medical Center, Sec. 6, Minquan E. Road, Taipei 11490, Taiwan. mctsai@ndmctsgh.edu.tw.
authors.forename: Min-Chien
authors.initials: MC
authors.lastname: Tsai
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001011:Aorta / Q000166:cytology; D002074:Butanones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D020212:Carotid Artery Injuries / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017536:Carotid Artery, Common / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007274:Injections, Intraperitoneal; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D002074:Butanones; D002317:Cardiovascular Agents; D018797:Cell Cycle Proteins; D010982:Platelet-Derived Growth Factor; D013450:Sulfones; C000590752:dihydroaustrasulfone alcohol