Altered expression of titin and contractile proteins in failing human myocardium.
Our own previous ultrastructural studies in human hearts with dilated cardiomyopathy and heart failure showed sarcomeric and cytoskeletal disarrangement. On the basis of these findings we tested the hypothesis that in cardiomyopathic failing hearts not only the sarcomere structure but also the organization and the amount of numerous contractile proteins are disturbed. Titin was included in this study because it is the elastic "third" filament of the sarcomere and also plays an important role as template for myosin and actin filaments in sarcomerogenesis. Human cardiac tissue obtained at the time of transplantation surgery was investigated using immunohistochemistry with monoclonal antibodies against titin, myosin, actin, tropomyosin, and troponin T. Additionally, isolated myocytes from rat or pig heart were used for the standardization of the localization pattern. In normal tissue, myosin and the thin filament complex showed a regular cross striation that was wider in myosin staining than for actin, troponin T, and tropomyosin corresponding with the different width of the A and I bands in the sarcomere. Titin localization in normal human and animal myocardium showed a regular cross striation pattern. In diseased cardiac tissue titin fluorescence intensity was reduced and frequently disorganization or almost complete loss of titin from many myocytes were present. Severe abnormalities of contractile proteins consisting of disarrangement or lack of filaments were also observed. Double staining procedures showed that in the same myocyte defects of the contractile apparatus were accompanied by a simultaneous reduction of titin indicating that the "third" sarcomeric filament system is involved in heart failure. Abnormalities of titin expression may be especially important because titin significantly influences sarcomeric elastic behaviour and is necessary as template for the organization of newly synthesized myosin and actin filaments. The loss of titin may contribute to the altered compliance in failing hearts. It is concluded that disorganization and loss of titin, myosin, and the thin filament complex are severe in the failing human heart because of dilated cardiomyopathy and that these changes may represent several of the most important components of the structural correlate of reduced cardiac function.
Hein
S
S
Max-Planck-Institute for Physiological and Clinical Research, Department of Experimental Cardiology, Bad Nauheim, Germany.
Scholz
D
D
Fujitani
N
N
Rennollet
H
H
Brand
T
T
Friedl
A
A
Schaper
J
J
D000328:Adult; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D064211:Connectin; D005260:Female; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009124:Muscle Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases; D012518:Sarcomeres / Q000378:metabolism / Q000648:ultrastructure
D064211:Connectin; D009124:Muscle Proteins; C577285:TTN protein, human; D011494:Protein Kinases