This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 114/2/150    most recent CIRCULATIONAHA.105.595918v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, S.-P. Articles by Kim, H.-S. Search for Related Content PubMed PubMed Citation Articles by Lee, S.-P. Articles by Kim, H.-S. Related Collections Angiogenesis Ischemic biology - basic studies Endothelium/vascular type/nitric oxide

(Circulation. 2006;114:150-159.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

Integrin-Linked Kinase, a Hypoxia-Responsive Molecule, Controls Postnatal Vasculogenesis by Recruitment of Endothelial Progenitor Cells to Ischemic Tissue

Seung-Pyo Lee, MD^*; Seock-Won Youn, MS^*; Hyun-Jai Cho, MD; Lian Li, BA; Tae-Youn Kim, BA; Hyung-Seon Yook, BA; Jae-Woong Chung, MS; Jin Hur, MS; Chang-Hwan Yoon, MD; Kyung-Woo Park, MD; Byung-Hee Oh, MD; Young-Bae Park, MD; Hyo-Soo Kim, MD

From the Department of Internal Medicine (S.-P.L., H.-J.C., C.-H.Y., K.-W.P., B.-H.O., Y.-B.P., H.-S.K.), Seoul National University College of Medicine, and Cardiovascular Laboratory (S.-P.L., S.-W.Y., H.-J.C., L.L., T.-Y.K., H.-S.Y., J.-W.C., J.H., C.-H.Y., K.-W.P., B.-H.O., Y.-B.P., H.-S.K.), Clinical Research Institute, Seoul National University Hospital, Seoul, Korea.

Correspondence to Hyo-Soo Kim, MD, PhD, or Young-Bae Park, MD, PhD, Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongro-gu, Seoul 110-744, South Korea. E-mail hyosoo{at}snu.ac.kr

Received October 17, 2005; revision received May 10, 2006; accepted May 12, 2006.

Background— Recruitment and adhesion of endothelial progenitor cells (EPCs) to hypoxic endothelial cells (ECs) is essential for vasculogenesis in ischemic tissue; little is known, however, about the key signals or intracellular signaling pathways involved in orchestrating the expression of adhesion molecules by ECs in response to hypoxia and how this is related to the recruitment of EPCs to the ischemic tissue. Here, we report that endogenous integrin-linked kinase (ILK) is a novel molecule that responds to hypoxia in ECs that regulates the expression of stromal cell–derived factor-1 (SDF-1) and intercellular adhesion molecule-1 (ICAM-1) through nuclear factor-B and hypoxia-inducible factor-1 and induces recruitment of EPCs to ischemic areas.

Methods and Results— Under hypoxia, both the endogenous amount and kinase activity of ILK were time-dependently upregulated in ECs, which was associated with increased ICAM-1 and SDF-1. This upregulation of ILK was mediated by stabilization of ILK by heat shock protein 90. ILK overexpression in normoxic ECs resulted in ICAM-1 and SDF-1 upregulation through dual control by nuclear factor-B and hypoxia-inducible factor-1. Blockade of ILK in hypoxic ECs significantly abrogated the expression of both molecules, which led to decreased EPC incorporation into ECs. A hindlimb ischemia model showed that ILK blockade significantly reduced EPC homing to ischemic limb and consequently led to poor neovascularization. Overexpression of ILK in the Matrigel plug significantly improved neovascularization in vivo, whereas the blockade of ILK resulted in the opposite effect.

Conclusions— Endogenous ILK is a novel and physiological upstream responder of numerous intracellular molecules involved in hypoxic stress in ECs and may control the recruitment of EPCs to ischemic tissue.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				L. Ding, L. Dong, X. Chen, L. Zhang, X. Xu, A. Ferro, and B. Xu Increased Expression of Integrin-Linked Kinase Attenuates Left Ventricular Remodeling and Improves Cardiac Function After Myocardial Infarction Circulation, September 1, 2009; 120(9): 764 - 773. [Abstract] [Full Text] [PDF]

				H.-J. Kang and H.-S. Kim Safety and efficacy of intracoronary infusion of mobilized peripheral blood stem cell in patients with myocardial infarction: MAGIC Cell-1 and MAGIC Cell-3-DES-trials Eur. Heart J. Suppl., December 1, 2008; 10(suppl_K): K39 - K43. [Abstract] [Full Text] [PDF]

				P. C. McDonald, A. B. Fielding, and S. Dedhar Integrin-linked kinase - essential roles in physiology and cancer biology J. Cell Sci., October 1, 2008; 121(19): 3121 - 3132. [Abstract] [Full Text] [PDF]

				M. S. Penn and A. A. Mangi Genetic Enhancement of Stem Cell Engraftment, Survival, and Efficacy Circ. Res., June 20, 2008; 102(12): 1471 - 1482. [Abstract] [Full Text] [PDF]

				A. Zampetaki, J. P. Kirton, and Q. Xu Vascular repair by endothelial progenitor cells Cardiovasc Res, June 1, 2008; 78(3): 413 - 421. [Abstract] [Full Text] [PDF]

				L. Lei, D. Liu, Y. Huang, I. Jovin, S.-Y. Shai, T. Kyriakides, R. S. Ross, and F. J. Giordano Endothelial Expression of 1 Integrin Is Required for Embryonic Vascular Patterning and Postnatal Vascular Remodeling Mol. Cell. Biol., January 15, 2008; 28(2): 794 - 802. [Abstract] [Full Text] [PDF]

				M. B. Joshi, D. Ivanov, M. Philippova, P. Erne, and T. J. Resink Integrin-linked kinase is an essential mediator for T-cadherin-dependent signaling via Akt and GSK3{beta} in endothelial cells FASEB J, October 1, 2007; 21(12): 3083 - 3095. [Abstract] [Full Text] [PDF]

				R. Knoll, R. Postel, J. Wang, R. Kratzner, G. Hennecke, A. M. Vacaru, P. Vakeel, C. Schubert, K. Murthy, B. K. Rana, et al. Laminin-{alpha}4 and Integrin-Linked Kinase Mutations Cause Human Cardiomyopathy Via Simultaneous Defects in Cardiomyocytes and Endothelial Cells Circulation, July 31, 2007; 116(5): 515 - 525. [Abstract] [Full Text] [PDF]