doi: 10.1161/ATVBAHA.108.174250
© 2008 American Heart Association, Inc.
Editorials |
A New Kid on the Block
PKD1: A Promising Target for Antiangiogenic Therapy?
From the Institut fuer umweltmedizinische Forschung at the University of Duesseldorf GmbH, Germany.
The formation of blood vessels through the process of angiogenesis is critical in normal vascular development and numerous vascular disorders. The most prominent stimulus for angiogenic processes in endothelial cells is vascular endothelial growth factor (VEGF), which regulates their migration, proliferation, and survival.1 The crucial role for this factor is documented by the lethal phenotype resulting from disruption of a single allele in mice.2,3 Binding of VEGF to its receptors activates several intracellular signaling molecules, among them phospholipase C
(PLC), protein kinase C (PKC), protein kinase D (PKD), and phosphatidyl-insitol-3 kinase (PI3K).1 The VEF-induced signaling events finally culminate in gene expression changes in the nucleus.
See accompanying article on page 1782
A key regulator of gene expression is chromatin structure, which is largely determined by the acetylation status of histones. In general, acetylation of these nucleosomal proteins by histone acetyl transferases (HATs) stimulates transcription, whereas deacetylation by histone deacetylases (HDACs) leads to transcriptional repression. The HDAC family comprises 18 members in humans, which are classified based on their homologies to yeast proteins.4 Class II HDACs appear to be dedicated to the control of tissue growth and development. Specifically, the class II enzyme HDAC7 is expressed exclusively in endothelial cells. Its disruption results in embryonic lethality by embryonic day 11 because of cardiovascular defects.5 Recently it has been shown that HDAC7 is critically involved in endothelial cell migration.6 However, the connection between VEGF, its target genes, and HDAC7 had not been uncovered until recently.
In this context, Ha et al, in this issue of ATVB, for the first time demonstrate that PKD1 is a VEGF-induced upstream regulator of HDAC7. Pharmacological inhibition and genetic ablation of PKD1 completely abolished VEGF-induced phosphorylation of HDAC7. This phosphorylation requires nuclear translocation of PKD1 (Figure) as a nonphophorylatable HDAC7 mutant is constitutively localized in the nucleus, excluding a shuttling process of HDAC7, which would allow cytoplasmic phosphorylation and sequestration in this compartment. The trigger for nuclear import of PKD1 could be its phosphorylation by PKC. However, the import mechanism is not well defined so far. It is known that phosphorylation of the amino terminus of the class II members HDAC4 and HDAC5 by calcium/calmodulin-dependent kinase or PKD creates docking sites for the 14-3-3 family of proteins, which promotes shuttling from the nucleus to the cytoplasm and thereby leads to derepression of HDAC target genes.7,8 Ha et al demonstrate that HDAC7 is exported from the nucleus in a PKD1-specific manner. The same observation was made in parallel by Wang and coauthors.9 To determine whether the interaction between HDAC7 and MEF2, a well-defined target for repression by HDAC7, confers VEGF-responsiveness to genes, Ha et al analyzed the MEF2 target gene matrix metalloproteinase (MMP) 10 (MMP10). Overexpression of a catalytically inactive PKD1 or a nonphosphorylatable HDAC7 abrogated VEGF-induced upregulation of MMP10. Interestingly, the authors also identified a new target of the VEGF-PKD1-HDAC7 axis, the membrane type MMP1 (MT-MMP1), which is important for angiogenesis in vivo.10 During angiogenesis MMPs degrade components of the extracellular matrix thereby permitting endothelial cells to migrate into the surrounding tissue. Therefore, their tight regulation is critical to maintain tissue allostasis, thus, VEGF-induced PKD1 actiavtion is one crucial player in this process. It has to be noted, that also MEF2-independent genes are upregulated on VEGF-induced nuclear export of HDAC7.9 Interference with MT-MMP1 expression or PKD1 and HDAC7 function severely reduced cell migration and tube formation in vitro. Importantly, Ha et al also show a crucial role for the PKD1-HDAC7 pathway in microvessel sprouting from aortic rings ex vivo.
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The cumulative evidence provided in the article offers new routes for therapeutic manipulation of the VEGF-PKD1-HDAC7 axis in angiogenesis-related diseases. The most attractive target for antiangiogenic therapies seems to be PKD1. A general strategy to inhibit kinases is the design of small molecules, which provide advantages over VEGF-directed antibodies already in clinical use (eg, Bevacizumab), including costs and the possibility to design a plethora of derivatives. One may also speculate that small molecule inhibitors of PKD1 could have less side effects than anti-VEGF antibodies, because sequestration of VEGF interferes with the functions of all its receptors. The ultimate drug would be a small compartment-specific molecule targeting exclusively nuclear PKD1.
In summary, the study of Ha et al describes some exciting novel findings which, as any good study, answers one and raises a bunch of new questions. Most importantly, new studies are needed to create specific PKD1 inhibitors and to test them and their side effects in animal models.
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Acknowledgments |
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Sources of funding
This work was supported, in part, by the Deutsche Forschungsgemeinschaft (HA2868/3-2) to J.H.
Disclosures
None.
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Footnotes |
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Correspondence to Judith Haendeler, PhD, Molecular Cell & Aging Research, IUF (Institut fuer Umweltmedizinische Forschung), at the University of Duesseldorf GmbH, Auf‘m Hennekamp 50, 40225 Duesseldorf, Germany. E-mail juhae001@uni-duesseldorf.de
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References |
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