This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 116/6/654    most recent CIRCULATIONAHA.106.672451v1 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 Hu, X. Articles by Rokosh, G. Search for Related Content PubMed PubMed Citation Articles by Hu, X. Articles by Rokosh, G. Related Collections Other myocardial biology Apoptosis Cell biology/structural biology Cell signalling/signal transduction Ischemic biology - basic studies Acute myocardial infarction Receptor pharmacology

(Circulation. 2007;116:654-663.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Stromal Cell–Derived Factor-1 Confers Protection Against Myocardial Ischemia/Reperfusion Injury

Role of the Cardiac Stromal Cell–Derived Factor-1–CXCR4 Axis

Xiaofeng Hu, MD, PhD; Shujing Dai, MD, PhD; Wen-Jian Wu, MSc; Wei Tan, MD; Xiaoping Zhu, MD; Jingyao Mu, MD; Yiru Guo, MD; Roberto Bolli, MD; Gregg Rokosh, PhD

From the Institute of Molecular Cardiology, Division of Cardiology, University of Louisville, Louisville, Ky.

Correspondence to Gregg Rokosh, PhD, Institute of Molecular Cardiology, 570 S Preston St, University of Louisville, Louisville, KY 40202. E-mail gregg.rokosh{at}louisville.edu

Received October 25, 2006; accepted May 29, 2007.

Background— Stromal cell–derived factor-1 (SDF-1) binding to its cognate receptor, CXCR4, regulates a variety of cellular functions such as stem cell homing, trafficking, and differentiation. However, the role of the SDF-1–CXCR4 axis in modulating myocardial ischemia/reperfusion injury is unknown.

Methods and Results— In mice subjected to ischemic preconditioning, myocardial SDF-1 mRNA was found to be increased 3 hours later (P<0.05). Myocardial SDF-1 and CXCR4 mRNA and protein were found to be expressed in both cardiac myocytes and fibroblasts. SDF-1 production increased significantly after 1 or 4 hours of hypoxia and 18 hours of reoxygenation in cultured myocytes (P<0.05) but did not change in fibroblast cultures. In isolated myocytes, CXCR4 activation by SDF-1 resulted in increased phosphorylation of both ERK 1/2 and AKT and decreased phosphorylation of JNK and p38. Cultured myocytes pretreated with SDF-1 were resistant to hypoxia/reoxygenation damage, exhibiting less lactate dehydrogenase release, trypan blue uptake, and apoptotic cell death (terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling assay) (P<0.05). This protective effect was blocked by the CXCR4 selective antagonist AMD3100. In vivo, administration of SDF-1 before 30 minutes of coronary occlusion followed by 4 hours of reperfusion decreased infarct size (P<0.05). The decrease in infarct size with SDF-1 administration also was blocked by AMD3100.

Conclusions— We conclude that SDF-1 and its receptor, CXCR4, constitute a paracrine or autocrine axis in cardiac myocytes that is activated in response to preconditioning and hypoxic stimuli, recruiting the antiapoptotic kinases ERK and AKT and promoting an antiapoptotic program that confers protection against ischemia/reperfusion damage.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				M. S. Penn Importance of the SDF-1:CXCR4 Axis in Myocardial Repair Circ. Res., May 22, 2009; 104(10): 1133 - 1135. [Full Text] [PDF]

				Y. L. Tang, W. Zhu, M. Cheng, L. Chen, J. Zhang, T. Sun, R. Kishore, M. I. Phillips, D. W. Losordo, and G. Qin Hypoxic Preconditioning Enhances the Benefit of Cardiac Progenitor Cell Therapy for Treatment of Myocardial Infarction by Inducing CXCR4 Expression Circ. Res., May 22, 2009; 104(10): 1209 - 1216. [Abstract] [Full Text] [PDF]

				T. Kamota, T.-S. Li, N. Morikage, M. Murakami, M. Ohshima, M. Kubo, T. Kobayashi, A. Mikamo, Y. Ikeda, M. Matsuzaki, et al. Ischemic pre-conditioning enhances the mobilization and recruitment of bone marrow stem cells to protect against ischemia/reperfusion injury in the late phase. J. Am. Coll. Cardiol., May 12, 2009; 53(19): 1814 - 1822. [Abstract] [Full Text] [PDF]

				X. Pi, Y. Wu, J. E. Ferguson III, A. L. Portbury, and C. Patterson SDF-1{alpha} stimulates JNK3 activity via eNOS-dependent nitrosylation of MKP7 to enhance endothelial migration PNAS, April 7, 2009; 106(14): 5675 - 5680. [Abstract] [Full Text] [PDF]

				T. Zhao, D. Zhang, R. W. Millard, M. Ashraf, and Y. Wang Stem cell homing and angiomyogenesis in transplanted hearts are enhanced by combined intramyocardial SDF-1{alpha} delivery and endogenous cytokine signaling Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H976 - H986. [Abstract] [Full Text] [PDF]

				P. J. Hohensinner, C. Kaun, K. Rychli, A. Niessner, S. Pfaffenberger, G. Rega, A. Furnkranz, P. Uhrin, J. Zaujec, T. Afonyushkin, et al. The inflammatory mediator oncostatin M induces stromal derived factor-1 in human adult cardiac cells FASEB J, March 1, 2009; 23(3): 774 - 782. [Abstract] [Full Text] [PDF]

				B.-C. Lee, H.-C. Hsu, W.-Y. I. Tseng, C.-Y. Chen, H.-J. Lin, Y.-L. Ho, M.-J. Su, and M.-F. Chen Cell therapy generates a favourable chemokine gradient for stem cell recruitment into the infarcted heart in rabbits Eur J Heart Fail, March 1, 2009; 11(3): 238 - 245. [Abstract] [Full Text] [PDF]