Abstract 1678: Kruppel-Like Factor 5 Directly Stimulates Cell Growth in Vascular Lesions
Introduction: KLF5 belongs to a family of zinc finger transcription factors known as the Sp/KLF factors. Past studies collectively have shown that expression of KLF5 is associated with proliferating smooth muscle cells in coronary lesions, that KLF5 can induce cell growth in non-cardiovascular cells, and for this factor to be pathologically induced. However, it had yet to be shown that KLF5 could in fact directly induce cell proliferation in the vascular lesion and cell which would be a prerequisite for further developing vascular therapies aimed at directly inhibiting KLF5 actions. In the present study, we have addressed the direct actions of KLF5 on cell growth in the vasculature.
Methods & Results: We performed adenovirus-mediated overexpression of KLF5 and another similar zinc finger transcription factor, Sp1, after balloon injury. Neointimal formation significantly increased in the KLF5 group (intima/media ratio 1.39 (SD 0.23)) compared to in the Sp1 group (I/M ratio 0.70 (SD 0.23)). The KLF5 group also showed increased cell proliferation rate using PCNA staining. Rat aortic vascular smooth muscle cells (VSMCs) transfected with KLF5 showed marked increase in cell proliferation and BrdU uptake. Cell cycle analysis also showed significant increase of S phase entry in the KLF5 group. Additionally, it was confirmed that transduction of KLF5 up regulates gene expression of cell cycle factors (e.g. cyclinD1). On the other hand, transfection with small interfering RNA resulted in impairment of VSMC cell proliferation and cell cycle progression recognized in KLF5 overexpression.
Conclusion: These findings suggest that KLF5 plays a central role in VSMC proliferative situation such as vascular remodeling through direct promotion of cell cycle and subsequent cell proliferation. Therapeutic intervention targeted against KLF5 may be potentially exploitable for SMC proliferative vascular pathology.