Nanae Kada

Regulation of Platelet-derived Growth Factor-A Chain by Krüppel-like Factor 5 NEW PATHWAY OF COOPERATIVE ACTIVATION WITH NUCLEAR FACTOR-κB

The transcription factor Krüppel-like factor 5 (KLF5) and its genetically downstream target gene platelet-derived growth factor-A (PDGF-A) chain are key factors in regulation of cardiovascular remodeling in response to stress. We show that KLF5 mediates a novel distinct delayed persistent induction of PDGF-A chain in response to the model agonist, phorbol ester, through a cis-element previously shown to mediate phorbol ester induction on to PDGF-A chain through the early growth response factor (Egr-1). Interestingly, the nuclear factor-κB (NF-κB) p50 subunit further cooperatively activates PDGF-A chain through protein-protein interaction with KLF5 but not Egr-1. RNA interference analysis confirmed that KLF5 and p50 are important for induction of PDGF-A chain. Collectively, we identify a novel regulatory pathway in which PDGF-A chain gene expression, under the control of KLF5, is cooperatively activated by the NF-κB p50 subunit and a pathophysiological stimulus.

Functional interaction between the transcription factor Krüppel-like factor 5 and poly(ADP-ribose) polymerase-1 in cardiovascular apoptosis.

Krüppel-like factor 5 (KLF5) is a transcription factor important in regulation of the cardiovascular response to external stress. KLF5 regulates pathological cell growth, and its acetylation is important for this effect. Its mechanisms of action, however, are still unclear. Analysis in KLF5-deficient mice showed that KLF5 confers apoptotic resistance in vascular lesions. Mechanistic analysis further showed that it specifically interacts with poly(ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme important in DNA repair and apoptosis. KLF5 interacted with a proteolytic fragment of PARP-1, and acetylation of KLF5 under apoptotic conditions increased their affinity. Moreover, KLF5 wild-type (but not a non-acetylatable point mutant) inhibited apoptosis as induced by the PARP-1 fragment. Collectively, we have found that KLF5 regulates apoptosis and targets PARP-1, and further, for acetylation to regulate these effects. Our findings thus implicate functional interaction between the transcription factor KLF5 and PARP-1 in cardiovascular apoptosis.

Acyclic retinoid inhibits functional interaction of transcription factors Krüppel-like factor 5 and retinoic acid receptor-alpha.

We show that transcription factor Krüppel‐like factor 5 (KLF5), which is important in cardiovascular remodeling, interacts with retinoic acid receptor‐alpha (RARα) to regulate downstream gene expression. Here, we investigated whether acyclic retinoid (ACR) regulates KLF5 and inhibits vascular remodeling. Co‐immunoprecipitation and pull‐down binding assay showed that ACR attenuates functional interaction of KLF5 and RARα. ACR affects KLF5 functions by regulating transactivation of platelet‐derived growth factor A (PDGF‐A) chain. ACR may be a new vascular therapy to target KLF5 in cardiovascular pathology.

Acyclic Retinoid Inhibits Neointima Formation Through Retinoic Acid Receptor Beta-Induced Apoptosis

Objectives—Acyclic retinoid (ACR) is a synthetic retinoid with a high safety profile that has been pursued with high expectations for therapeutic use in prevention (recurrence) and treatment of malignancies. With the objective of addressing the therapeutic potential in the cardiovasculature, namely neointima formation, effects of ACR on neointima formation and the involved mechanisms were investigated. Methods and Results—ACR was administered to cuff-injured mice which showed inhibition of neointima formation. Investigation of involved mechanisms at the cellular and molecular levels showed that ACR induces apoptosis of neointimal cells and this to be mediated by selective induction of retinoic-acid receptor β (RARβ) which shows growth inhibitory and proapoptotic effects on smooth muscle cells. Conclusion—We show that ACR inhibits neointima formation by inducing RARβ which in turn inhibits cell growth and induces apoptosis. The retinoid, ACR, may be potentially exploitable for treatment and prevention of neointima formation.