Histone Deacetylase 9 Promotes Angiogenesis by Targeting the Antiangiogenic MicroRNA-17–92 Cluster in Endothelial Cells

David Kaluza; Jens Kroll; Sabine Gesierich; Yosif Manavski; Jes-Niels Boeckel; Carmen Doebele; Arthur Zelent; Lothar Rössig; Andreas M Zeiher; Hellmut G Augustin; Carmen Urbich; Stefanie Dimmeler

doi:10.1161/ATVBAHA.112.300415

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Histone Deacetylase 9 Promotes Angiogenesis by Targeting the Antiangiogenic MicroRNA-17–92 Cluster in Endothelial Cells

Journal article

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Peer reviewed

Histone Deacetylase 9 Promotes Angiogenesis by Targeting the Antiangiogenic MicroRNA-17–92 Cluster in Endothelial Cells

David Kaluza, Jens Kroll, Sabine Gesierich, Yosif Manavski, Jes-Niels Boeckel, Carmen Doebele, Arthur Zelent, Lothar Rössig, Andreas M Zeiher, Hellmut G Augustin, …

Arteriosclerosis, thrombosis, and vascular biology, Vol.33(3), pp.533-543

2013-03

DOI: https://doi.org/10.1161/ATVBAHA.112.300415

PMID: 23288173

Abstract

Objective— Histone deacetylases (HDACs) modulate gene expression by deacetylation of histone and nonhistone proteins. Several HDACs control angiogenesis, but the role of HDAC9 is unclear. Methods and Results— Here, we analyzed the function of HDAC9 in angiogenesis and its involvement in regulating microRNAs. In vitro, silencing of HDAC9 reduces endothelial cell tube formation and sprouting. Furthermore, HDAC9 silencing decreases vessel formation in a spheroid-based Matrigel plug assay in mice and disturbs vascular patterning in zebrafish embryos. Genetic deletion of HDAC9 reduces retinal vessel outgrowth and impairs blood flow recovery after hindlimb ischemia. Consistently, overexpression of HDAC9 increases endothelial cell sprouting, whereas mutant constructs lacking the catalytic domain, the nuclear localization sequence, or sumoylation site show no effect. To determine the mechanism underlying the proangiogenic effect of HDAC9, we measured the expression of the microRNA (miR)-17–92 cluster, which is known for its antiangiogenic activity. We demonstrate that silencing of HDAC9 in endothelial cells increases the expression of miR-17–92. Inhibition of miR-17–20a rescues the sprouting defects induced by HDAC9 silencing in vitro and blocking miR-17 expression partially reverses the disturbed vascular patterning of HDAC9 knockdown in zebrafish embryos. Conclusion— We found that HDAC9 promotes angiogenesis and transcriptionally represses the miR-17–92 cluster.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.25 Molecular & Cell Biology - Cancer, Autophagy & Apoptosis; 1.25.1461 Histone Deacetylase
Web Of Science research areas: Hematology; Peripheral Vascular Disease
ESI research areas: Clinical Medicine

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Title: Histone Deacetylase 9 Promotes Angiogenesis by Targeting the Antiangiogenic MicroRNA-17–92 Cluster in Endothelial Cells
Creators: David Kaluza - From the Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, University of Frankfurt, Frankfurt, Germany (D.K., Y.M., J.-N.B., C.D., L.R., C.U., S.D.); Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany (J.K., S.G., H.G.A.); Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (J
Jens Kroll - From the Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, University of Frankfurt, Frankfurt, Germany (D.K., Y.M., J.-N.B., C.D., L.R., C.U., S.D.); Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany (J.K., S.G., H.G.A.); Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (J
Sabine Gesierich - From the Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, University of Frankfurt, Frankfurt, Germany (D.K., Y.M., J.-N.B., C.D., L.R., C.U., S.D.); Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany (J.K., S.G., H.G.A.); Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (J
Yosif Manavski - From the Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, University of Frankfurt, Frankfurt, Germany (D.K., Y.M., J.-N.B., C.D., L.R., C.U., S.D.); Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany (J.K., S.G., H.G.A.); Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (J
Jes-Niels Boeckel - From the Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, University of Frankfurt, Frankfurt, Germany (D.K., Y.M., J.-N.B., C.D., L.R., C.U., S.D.); Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany (J.K., S.G., H.G.A.); Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (J
Carmen Doebele - From the Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, University of Frankfurt, Frankfurt, Germany (D.K., Y.M., J.-N.B., C.D., L.R., C.U., S.D.); Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany (J.K., S.G., H.G.A.); Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (J
Arthur Zelent - From the Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, University of Frankfurt, Frankfurt, Germany (D.K., Y.M., J.-N.B., C.D., L.R., C.U., S.D.); Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany (J.K., S.G., H.G.A.); Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (J
Lothar Rössig - From the Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, University of Frankfurt, Frankfurt, Germany (D.K., Y.M., J.-N.B., C.D., L.R., C.U., S.D.); Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany (J.K., S.G., H.G.A.); Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (J
Andreas M Zeiher - From the Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, University of Frankfurt, Frankfurt, Germany (D.K., Y.M., J.-N.B., C.D., L.R., C.U., S.D.); Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany (J.K., S.G., H.G.A.); Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (J
Hellmut G Augustin - From the Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, University of Frankfurt, Frankfurt, Germany (D.K., Y.M., J.-N.B., C.D., L.R., C.U., S.D.); Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany (J.K., S.G., H.G.A.); Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (J
Carmen Urbich - From the Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, University of Frankfurt, Frankfurt, Germany (D.K., Y.M., J.-N.B., C.D., L.R., C.U., S.D.); Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany (J.K., S.G., H.G.A.); Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (J
Stefanie Dimmeler - From the Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, University of Frankfurt, Frankfurt, Germany (D.K., Y.M., J.-N.B., C.D., L.R., C.U., S.D.); Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), Heidelberg, Germany (J.K., S.G., H.G.A.); Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (J
Publication Details: Arteriosclerosis, thrombosis, and vascular biology, Vol.33(3), pp.533-543
Language: English
Resource Type: Journal article
PMID: 23288173
Record Identifier: 991031613667202976