Loss of beta1D-integrin function in human ischemic cardiomyopathy.
Integrins play a pivotal role in cardiomyocyte survival and function, with integrin loss leading to myocyte apoptosis and heart failure. The aim of this study was to characterize whether regulation of integrins may contribute to cardiac remodeling in human ischemic cardiomyopathy (ICM). Myocardial tissues of the left ventricle were obtained from patients with ICM (n = 8) undergoing cardiac transplantation and from unused donor hearts (NF, n = 8). In addition, tissue samples from patients with dilated cardiomyopathy (DCM, n = 5) were analyzed. Expression of integrins beta(1)D and beta(3), the effector proteins focal adhesion kinase (FAK) and melusin, and FAK phosphorylation were examined by Western blotting, real-time-PCR and immunofluorescence analysis, respectively. Beta(1)D-integrin protein was decreased in ICM vs. NF by 36%. Beta(1)D-integrin mRNA levels and beta(1)D-integrin shedding were unchanged. Corresponding to beta(1)D-integrin regulation, FAK and phosphorylated FAK were decreased in ICM vs. NF by 54% and 49%, respectively. beta(3)-integrin and melusin were not altered in ICM. As a mediator of integrin effects, AKT kinase activity was examined. In parallel to beta(1)D-integrin and FAK, AKT activity was decreased in ICM by 44%. In contrast, none of the proteins were significantly altered in DCM compared to NF. Integrins and integrin signaling are regulated differentially in ICM and DCM with a decrease of beta(1)D-integrin and FAK in ICM. The loss of the beta(1)Dintegrin-FAK-complex in ICM was paralleled by a reduced AKT activity supporting in vitro data which demonstrate the pivotal role of intact integrin function in anti-apoptotic signaling and cell survival.
Pfister
Roman
R
Dept. III of Internal Medicine, University of Cologne, Josef-Stelzmann-Str. 9, 50924, Cologne, Germany.
Acksteiner
Christain
C
Baumgarth
Jonathan
J
Burst
Volker
V
Geissler
Hans J
HJ
Margulies
Kenneth B
KB
Houser
Steven
S
Bloch
Wilhelm
W
Flesch
Markus
M
D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D005260:Female; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1 / Q000096:biosynthesis*; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D066298:In Vitro Techniques; D019012:Integrin beta1 / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000096:biosynthesis*; D017202:Myocardial Ischemia / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D003598:Cytoskeletal Proteins; C492400:ITGB1BP2 protein, human; D019012:Integrin beta1; D009124:Muscle Proteins; D012333:RNA, Messenger; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human