Scoparone interferes with STAT3-induced proliferation of vascular smooth muscle cells.
Scoparone, which is a major constituent of Artemisia capillaries, has been identified as an anticoagulant, hypolipidemic, vasorelaxant, anti-oxidant and anti-inflammatory drug, and it is used for the traditional treatment of neonatal jaundice. Therefore, we hypothesized that scoparone could suppress the proliferation of VSMCs by interfering with STAT3 signaling. We found that the proliferation of these cells was significantly attenuated by scoparone in a dose-dependent manner. Scoparone markedly reduced the serum-stimulated accumulation of cells in the S phase and concomitantly increased the proportion of cells in the G0/G1 phase, which was consistent with the reduced expression of cyclin D1, phosphorylated Rb and survivin in the VSMCs. Cell adhesion markers, such as MCP-1 and ICAM-1, were significantly reduced by scoparone. Interestingly, this compound attenuated the increase in cyclin D promoter activity by inhibiting the activities of both the WT and active forms of STAT3. Similarly, the expression of a cell proliferation marker induced by PDGF was decreased by scoparone with no change in the phosphorylation of JAK2 or Src. On the basis of the immunofluorescence staining results, STAT3 proteins phosphorylated by PDGF were predominantly localized to the nucleus and were markedly reduced in the scoparone-treated cells. In summary, scoparone blocks the accumulation of STAT3 transported from the cytosol to the nucleus, leading to the suppression of VSMC proliferation through G1 phase arrest and the inhibition of Rb phosphorylation. This activity occurs independent of the form of STAT3 and upstream of kinases, such as Jak and Src, which are correlated with abnormal vascular remodeling due to the presence of an excess of growth factors following vascular injury. These data provide convincing evidence that scoparone may be a new preventative agent for the treatment of cardiovascular diseases.
Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Sungmi
S
Park
BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Jeong-Kook
JK
Kim
BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Chang Joo
CJ
Oh
Department of Biomedical Science, Kyungpook National University School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Seung Hee
SH
Choi
Departments of Internal Medicine, Kyungpook National University School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Jae-Han
JH
Jeon
1] Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University School of Medicine, Kyungpook National University, Daegu, Republic of Korea [2] BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University School of Medicine, Kyungpook National University, Daegu, Republic of Korea [3] Department of Biomedical Science, Kyungpook National University School of Medicine, Kyungpook National University, Daegu, Republic of Korea [4] Departments of Internal Medicine, Kyungpook National University School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
In-Kyu
IK
Lee
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000077214:Becaplermin; D015415:Biomarkers; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003374:Coumarins / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D051381:Rats; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic
D015415:Biomarkers; D018797:Cell Cycle Proteins; D003374:Coumarins; D020574:Proto-Oncogene Proteins c-sis; D050796:STAT3 Transcription Factor; D000077214:Becaplermin; C018145:scoparone