Abstract
The myocardium responds to hemodynamic stress through cellular growth and organ hypertrophy. The impact of cytoskeletal elements on this process, however, is not fully understood. While α-actin in cardiomyocytes governs muscle contraction in combination with the myosin motor, the exact role of β-actin has not been established. We hypothesized that in adult cardiomyocytes, as in non-myocytes, β-actin can facilitate cytoskeletal rearrangement within cytoskeletal structures such as Z-discs. Using a feline right ventricular pressure overload (RVPO) model, we measured the level and distribution of β-actin in normal and pressure overloaded myocardium. Resulting data demonstrated enriched levels of β-actin and enhanced translocation to the Triton-insoluble cytoskeletal and membrane skeletal complexes. In addition, RVPO in vivo and in vitro hypertrophic stimulation with endothelin (ET) or insulin in isolated adult cardiomyocytes enhanced the content of polymerized fraction (F-actin) of β-actin. To determine the localization and dynamics of β-actin, we adenovirally expressed GFP-tagged β-actin in isolated adult cardiomyocytes. The ectopically expressed β-actin-GFP localized to the Z-discs, costameres, and cell termini. Fluorescence recovery after photobleaching (FRAP) measurements of β-actin dynamics revealed that β-actin at the Z-discs is constantly being exchanged with β-actin from cytoplasmic pools and that this exchange is faster upon hypertrophic stimulation with ET or insulin. In addition, in electrically stimulated isolated adult cardiomyocytes, while β-actin overexpression improved cardiomyocyte contractility, immunoneutralization of β-actin resulted in a reduced contractility suggesting that β-actin could be important for the contractile function of adult cardiomyocytes. These studies demonstrate the presence and dynamics of β-actin in the adult cardiomyocyte and reinforce its usefulness in measuring cardiac cytoskeletal rearrangement during hypertrophic stimulation.
Highlights
Actin is a ubiquitously expressed and highly conserved cytoskeletal protein essential for numerous cellular processes including cell attachment, spreading, cytokinesis, vesicular trafficking, transcription, translation, and ion transport [1]
A feline right ventricular pressure overload (RVPO) model was used to study the role of b-actin in cardiac hypertrophy, upon which the pulmonary artery was ligated with a 3.2 mm internal diameter band which doubles the right ventricle (RV) pressure while the left ventricle (LV) pressure remains unchanged [20]
While it is conceivable that cardiomyocyte structural alterations such as growth and remodeling require coupling with actin dynamics, any evidence that a specific isoform of actin is involved in such phenotypic modification in cardiomyocytes has yet to be established
Summary
Actin is a ubiquitously expressed and highly conserved cytoskeletal protein essential for numerous cellular processes including cell attachment, spreading, cytokinesis, vesicular trafficking, transcription, translation, and ion transport [1]. The expression pattern mimicking the fetal stages can be observed both in adult cardiomyocytes undergoing hypertrophy or in culture in the presence of various hypertrophic stimuli [1]. B-Actin is expressed in all four chambers of the heart as well as in cultured adult cardiomyocytes [2,3]. B-actin-containing molecular complexes are critical in cytoskeletal rearrangement upon cell shape modulating signals. Cardiomyocytes express b-actin in considerable amounts, whether it participates in cytoskeletal rearrangement upon hypertrophic stimulation remains poorly understood
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