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(Circulation. 2006;114:2271-2279.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

Integrin-Linked Kinase Expression Is Elevated in Human Cardiac Hypertrophy and Induces Hypertrophy in Transgenic Mice

Huanzhang Lu, PhD; Paul W. M. Fedak, MD; Xiaojing Dai, MD; Changqing Du, MD; Yu-Qing Zhou, MD; Mark Henkelman, PhD; Perry S. Mongroo, PhD; Arthur Lau, MD; Hideaki Yamabi, MD; Aleksander Hinek, MD, PhD; Mansoor Husain, MD; Gregory Hannigan, PhD; John G. Coles, MD

From the Cancer Research Program, Research Institute (H.L., P.S.M., G.H.), Division of Cardiovascular Research (P.W.M.F., X.D., C.D., A.L., H.Y., A.H., J.G.C.), and Mouse Imaging Centre (M.H.), Hospital for Sick Children, University of Toronto, and Toronto General Hospital Research Institute (Y.-Q.Z.), Division of Cardiology, Department of Medicine, University Health Network (M.H.), and Department of Laboratory Medicine and Pathobiology (G.H.), University of Toronto, Toronto, Ontario, Canada.

Correspondence to Dr Gregory Hannigan, Cancer and Blood Research, Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada (e-mail gregory.hannigan{at}sickkids.ca); or Dr J.G. Coles, Division of Cardiovascular Surgery, Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada (e-mail john.coles@sickkids.ca).

Received June 2, 2006; revision received July 27, 2006; accepted August 7, 2006.

Background— Although numerous signaling pathways are known to be activated in experimental cardiac hypertrophy, the molecular basis of the hypertrophic response inherent in human heart diseases remains largely unknown. Integrin-linked kinase (ILK) is a multifunctional protein kinase that physically links ß-integrins with the actin cytoskeleton, suggesting a potential mechanoreceptor role.

Methods and Results— Here, we show a marked increase in ILK protein levels in hypertrophic ventricles of patients with congenital and acquired outflow tract obstruction. This increase in ILK was associated with activation of the Rho family guanine triphosphatases, Rac1 and Cdc42, and known hypertrophic signaling kinases, including extracellular signal-related kinases (ERK1/2) and p70 S6 kinase. Transgenic mice with cardiac-specific expression of a constitutively active ILK (ILK^S343D) or wild-type ILK (ILK^WT) exhibited a compensated ventricular hypertrophic phenotype and displayed an activation profile of guanine triphosphatases and downstream protein kinases concordant with that seen in human hypertrophy. In contrast, transgenic mice with cardiomyocyte-restricted expression of a kinase-inactive ILK (ILK^R211A) were unable to mount a compensatory hypertrophic response to angiotensin II in vivo.

Conclusions— Taken together, these results identify ILK-regulated signaling as a broadly adaptive hypertrophic response mechanism relevant to a wide range of clinical heart disease.

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