Integrin-linked kinase is a central mediator in angiotensin II type 1- and chemokine receptor CXCR4 signaling in myocardial hypertrophy.
Inflammation and pro-hypertrophic signaling are important for development and progression of myocardial hypertrophy (LVH) and chronic heart failure (CHF). Here we investigated the relevance of integrin-linked kinase (ILK) for chemokine receptor CXCR4- and angiotensin II type 1-triggered signaling and its regulation and role in cardiac remodeling. Using ELISA, real-time-PCR, and Western blotting, the present study demonstrates that SDF-1 and its receptor CXCR4 are up-regulated in plasma and left ventricles, respectively, in mouse models of cardiac hypertrophy (transaortic constriction, transgenic cardiac-specific overexpression of rac1) and in human CHF in association with increased cardiac ILK-expression. In isolated cardiomyocytes, ILK is activated by CXCR4-ligation and necessary for SDF-1-triggered activation of rac1, NAD(P)H oxidase, and release of reactive oxygen species. Importantly, the pro-hypertrophic peptide angiotensin II induces ILK-activation dependent on rac1 in cardiomyocytes, where ILK is necessary for angiotensin II-mediated stimulation of hypertrophy genes and protein synthesis. We conclude that in both SDF-1- and angiotensin II-triggered signaling, ILK is a central mediator of rac1-induced oxidative stress and myocardial hypertrophy.
Bettink
Stephanie I
SI
Klinik für Innere Medizin III, Kardiologie, Angiologie, Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, 66421 Homburg/Saar, Germany.
Werner
Christian
C
Chen
Chia-Hui
CH
Müller
Patrick
P
Schirmer
Stephan H
SH
Walenta
Katrin L
KL
Böhm
Michael
M
Laufs
Ulrich
U
Friedrich
Erik B
EB
D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000099200:Scaffold Protein ILK
D054377:Chemokine CXCL12; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D019718:Receptors, CXCR4; D020830:rac1 GTP-Binding Protein; D000099200:Scaffold Protein ILK; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human