Increased expression of cytoskeletal, linkage, and extracellular proteins in failing human myocardium.
Experimental studies have shown that in hypertrophy and heart failure, accumulation of microtubules occurs that impedes sarcomere motion and contributes to decreased ventricular compliance. We tested the hypothesis that these changes are present in the failing human heart and that an entire complex of structural components, including cytoskeletal, linkage, and extracellular proteins, are involved in causing functional deterioration. In explanted human hearts failing because of dilated cardiomyopathy (ejection fraction </=20%), expression of alpha- and beta-tubulin, desmin, vinculin, fibronectin, and vimentin was determined by Northern and Western blot analysis and compared with normal myocardium from explants not used for transplantation. The mRNA for alpha- and beta-tubulin was increased to 2.4-fold (P<0.01) and 1.25-fold (NS), respectively; for desmin, 1.2-fold (P<0.05); for fibronectin, 5-fold (P<0.001); and for vimentin, 1.7-fold (P<0.05). Protein levels for alpha-tubulin increased 2.6-fold (P<0.02); for beta-tubulin, 1.2-fold (P<0.005); for desmin, 2.1-fold (P<0.001); for vinculin, 1.2-fold (P<0.005); for fibronectin, 2.9-fold (P<0.001); and for vimentin, 1.5-fold (P<0. 005). Confocal microscopy showed augmentation and disorganization of all proteins studied. In combination with the loss of myofilaments and sarcomeric skeleton previously reported, these changes suggest cardiomyocyte remodeling. Increased fibronectin and elevated interstitial cellularity (vimentin labeling) indicate progressive fibrosis. The present results suggest a causative role of cytoskeletal abnormalities and myofilament loss for intrinsic contractile and diastolic dysfunction in failing hearts.
Heling
A
A
Department of Experimental Cardiology, Max Planck Institute, and Department of Cardiac Surgery, Bad Nauheim, Germany.
Zimmermann
R
R
Kostin
S
S
Maeno
Y
Y
Hein
S
S
Devaux
B
B
Bauer
E
E
Klövekorn
W P
WP
Schlepper
M
M
Schaper
W
W
Schaper
J
J
D000328:Adult; D009202:Cardiomyopathies / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis*; D005260:Female; D005353:Fibronectins / Q000096:biosynthesis; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D016596:Vinculin / Q000096:biosynthesis
D003598:Cytoskeletal Proteins; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D016596:Vinculin