Impairment of ultrastructure and cytoskeleton during progression of cardiac hypertrophy to heart failure.
Studies at the morphological and molecular level have found that transgenic (Tg) mice that overexpress myotrophin in the heart develop hypertrophy at the early age of 4 weeks; this condition worsens to heart failure (HF) at approximately 36 weeks. However, how the sustained effects of alteration in cytoarchitecture of the contractile machinery lead to malfunction of the normal heart remains unclear. Our data have shown that at 4 weeks, the cytoarchitecture observed in left ventricular (LV) tissue samples of Tg mice is similar to that of wild-type (WT) mice. However, as the disease progresses, cardiomyocytes show deterioration in some mitochondrial as well as myofibril features, evidenced by swelling of mitochondria, misalignment of myofibril structure, and blurring as well as breakage of Z-lines. At 36 weeks of age, Tg mice (the group in transition from hypertrophy to HF) show significant degenerative changes in cardiomyocytes, including swelling of mitochondria, disruption of the nuclear membrane, and absence of myofibril structure. Besides these, formation of myelin bodies was also observed, a feature typically found in human hearts with HF. Changes in Z-line architecture were further confirmed by alteration in the gene expression profile of desmin and tubulin, the two main cytoskeletal proteins. We thus conclude that Tg mice overexpressing myotrophin show no visible changes in the initiation phase (4 weeks); however, as the disease progresses, alterations in the cytoskeleton are found during the transition phase from hypertrophy to HF (36 weeks onward). Our data suggest that treatment for prevention/reversal of hypertrophy should start at the early stage of hypertrophy to prevent its transition to HF.
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Anasuya
A
Gupta
Sudhiranjan
S
Gupta
David
D
Young
Biswajit
B
Das
James
J
McMahon
Subha
S
Sen
D000818:Animals; D006332:Cardiomegaly / Q000473:pathology* / Q000503:physiopathology; D003893:Desmin / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D006333:Heart Failure / Q000473:pathology* / Q000503:physiopathology; D006352:Heart Ventricles / Q000503:physiopathology / Q000648:ultrastructure*; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000502:physiology / Q000648:ultrastructure*; D009206:Myocardium / Q000648:ultrastructure*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure*; D009210:Myofibrils / Q000473:pathology / Q000648:ultrastructure; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
D003893:Desmin; D014404:Tubulin