Increased Expression of Cytoskeletal, Linkage, and Extracellular Proteins in Failing Human Myocardium

Author:

Heling Annette1,Zimmermann René1,Kostin Sawa1,Maeno Yoshi1,Hein Stefan1,Devaux Bruno1,Bauer Erwin1,Klövekorn Wolf-Peter1,Schlepper Martin1,Schaper Wolfgang1,Schaper Jutta1

Affiliation:

1. From the Department of Experimental Cardiology (A.H., S.K., Y.M., M.S., W.S., J.S.), Max Planck Institute, and Department of Cardiac Surgery (R.Z., S.H., E.B., W.-P.K.), Kerckhoff-Clinic, Bad Nauheim, Germany, and Centre Hospitalier (B.D.), Université de Rouen, France.

Abstract

Abstract —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 α- and β-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 α- and β-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 α-tubulin increased 2.6-fold ( P <0.02); for β-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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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