Transcriptional regulation of Pim-1 kinase in vascular smooth muscle cells and its role for proliferation.
The Ser/Thr-protein kinase Pim-1 has been discovered as a novel transducer of survival- and cell cycle promoting signals in the hematopoietic cell system. Although its significance for proliferation of vascular smooth muscle cells (VSMC) in vitro and neointima formation in vivo has been suggested recently, the mechanism has barely been characterized. This study aimed to foster the understanding of Pim-1 expression and regulation in murine VSMC in response to factors typically present within the atherosclerotic plaque. While oxidative stress, VEGF-A165 and angiotensin II did not have any effect on Pim-1 expression, VSMC strongly increased (3-fold) Pim-1 mRNA upon stimulation with PDGF(bb), followed by its protein upregulation. Half life of Pim-1 RNA and protein were determined to be 25 min and 6 h, respectively. PDGF(bb) induced a strong, 10-fold increase in BrdU-uptake, a marker of proliferation. This was effectively blocked by either Pim-1-specific inhibitor quercetagetin or adenovirally introduced Pim-1 shRNA. We further identified the signaling pathways linking PDGF(bb) to Pim-1 in VSMC: as expected, we determined transcriptional stimulation of Pim-1 via Janus-activated kinase (Jak), but also an additional pathway involving protein kinase C (PKC) and the mitogen-activated protein kinase Mek1/2. Blockade of Akt signaling did, however, not interfere with Pim-1 upregulation, suggesting an independence of either survival system. PDGF(bb)-induced proliferation of VSMC is partly attributed to transcriptionally upregulated Pim-1 and was assigned to distinct cell signaling. Our findings help to understand the fundamental processes of vasculoproliferative diseases thus opening avenues for its prevention and treatment.
Willert
Manuela
M
Internal Medicine, Department of Cardiology and Intensive Care, University of Technology Dresden, Dresden, Germany.
Augstein
Antje
A
Poitz
David M
DM
Schmeisser
Alexander
A
Strasser
Ruth H
RH
Braun-Dullaeus
Ruediger Christian
RC
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D053612:Janus Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*
D010982:Platelet-Derived Growth Factor; D053612:Janus Kinases; C496636:Pim1 protein, mouse; D051573:Proto-Oncogene Proteins c-pim-1; D011493:Protein Kinase C; D020929:Mitogen-Activated Protein Kinase Kinases