Deletion of Krüppel-like factor 4 in endothelial and hematopoietic cells enhances neointimal formation following vascular injury

Tadashi Yoshida, Maho Yamashita, Chihiro Horimai, Matsuhiko Hayashi
Journal of the American Heart Association 2014 January 27, 3 (1): e000622

BACKGROUND: Krüppel-like factor 4 (Klf4) is involved in a variety of cellular functions by activating or repressing the transcription of multiple genes. Results of previous studies showed that tamoxifen-inducible global deletion of the Klf4 gene in mice accelerated neointimal formation following vascular injury, in part via enhanced proliferation of smooth muscle cells (SMCs). Because Klf4 is also expressed in non-SMCs including endothelial cells (ECs), we determined if Tie2 promoter-dependent deletion of Klf4 in ECs and hematopoietic cells affected injury-induced neointimal formation.

METHODS AND RESULTS: Klf4 conditional knockout (cKO) mice were generated by breeding Tie2-Cre mice and Klf4 floxed mice, and their phenotype was analyzed after carotid ligation injury. Results showed that injury-induced repression of SMC differentiation markers was unaffected by Tie2 promoter-dependent Klf4 deletion. However, of interest, neointimal formation was significantly enhanced in Klf4-cKO mice 21 days following carotid injury. Moreover, Klf4-cKO mice exhibited an augmented proliferation rate, enhanced accumulation of macrophages and T lymphocytes, and elevated expression of cell adhesion molecules including vascular cell adhesion molecule-1 (Vcam1) and E-selectin in injured arteries. Mechanistic analyses in cultured ECs revealed that Klf4 inhibited tumor necrosis factor-α-induced expression of Vcam1 through blocking the binding of nuclear factor-κB to the Vcam1 promoter.

CONCLUSIONS: These results provide evidence that Klf4 in non-SMCs such as ECs regulates neointimal formation by repressing arterial inflammation following vascular injury.

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