Calcium-independent negative inotropy by beta-myosin heavy chain gene transfer in cardiac myocytes
| Autor: | Todd J. Herron, Terri G. Edwards, Joseph M. Metzger, Ekaterina V Fomicheva, Lakshmi Mundada, Rene Vandenboom |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
medicine.medical_specialty
Myofilament Physiology macromolecular substances Biology Sarcomere Contractility Ventricular Myosins Internal medicine Myosin medicine Myocyte Animals Myocytes Cardiac Cells Cultured Myosin Heavy Chains Cardiac myocyte Genetic transfer Gene Transfer Techniques musculoskeletal system Myocardial Contraction Rats Endocrinology Gene Expression Regulation Calcium medicine.symptom Cardiology and Cardiovascular Medicine tissues Muscle contraction |
| Zdroj: | Circulation research. 100(8) |
| ISSN: | 1524-4571 |
| Popis: | Increased relative expression of the slow molecular motor of the heart (β-myosin heavy chain [MyHC]) is well known to occur in many rodent models of cardiovascular disease and in human heart failure. The direct effect of increased relative β-MyHC expression on intact cardiac myocyte contractility, however, is unclear. To determine the direct effects of increased relative β-MyHC expression on cardiac contractility, we used acute genetic engineering with a recombinant adenoviral vector (AdMYH7) to genetically titrate β-MyHC protein expression in isolated rodent ventricular cardiac myocytes that predominantly expressed α-MyHC (fast molecular motor). AdMYH7-directed β-MyHC protein expression and sarcomeric incorporation was observed as soon as 1 day after gene transfer. Effects of β-MyHC expression on myocyte contractility were determined in electrically paced single myocytes (0.2 Hz, 37°C) by measuring sarcomere shortening and intracellular calcium cycling. Gene transfer-based replacement of α-MyHC with β-MyHC attenuated contractility in a dose-dependent manner, whereas calcium transients were unaffected. For example, when β-MyHC expression accounted for ≈18% of the total sarcomeric myosin, the amplitude of sarcomere-length shortening (nanometers, nm) was depressed by 42% (151.0±10.7 [control] versus 87.0±5.4 nm [AdMYH7 transduced]); and genetic titration of β-MyHC, leading to 38% β-MyHC content, attenuated shortening by 57% (138.9±13.0 versus 59.7±7.1 nm). Maximal isometric cross-bridge cycling rate was also slower in AdMYH7-transduced myocytes. Results indicate that small increases of β-MyHC expression (18%) have Ca 2+ transient-independent physiologically relevant effects to decrease intact cardiac myocyte function. We conclude that β-MyHC is a negative inotrope among the cardiac myofilament proteins. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|