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Circulation Research. 2007;100:1182-1190
Published online before print March 15, 2007, doi: 10.1161/01.RES.0000264102.00706.4e
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(Circulation Research. 2007;100:1182.)
© 2007 American Heart Association, Inc.


Cellular Biology

Calcium-Independent Negative Inotropy by ß-Myosin Heavy Chain Gene Transfer in Cardiac Myocytes

Todd J. Herron, Rene Vandenboom, Ekaterina Fomicheva, Lakshmi Mundada, Terri Edwards, Joseph M. Metzger

From the Department of Molecular & Integrative Physiology (T.J.H., R.V., E.F., L.M., T.E., J.M.M.) and Department of Internal Medicine–Cardiology (T.J.H. and J.M.M.), University of Michigan, Ann Arbor. Current address for R.V.: Brock University, St. Catharines, Ontario, Canada.

Correspondence to Todd J. Herron, PhD, Department of Molecular & Integrative Physiology, 1301 E Catherine St, University of Michigan, Ann Arbor, MI 48109-0622. E-mail toddherr{at}umich.edu

Increased relative expression of the slow molecular motor of the heart (ß-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 ß-MyHC expression on intact cardiac myocyte contractility, however, is unclear. To determine the direct effects of increased relative ß-MyHC expression on cardiac contractility, we used acute genetic engineering with a recombinant adenoviral vector (AdMYH7) to genetically titrate ß-MyHC protein expression in isolated rodent ventricular cardiac myocytes that predominantly expressed {alpha}-MyHC (fast molecular motor). AdMYH7-directed ß-MyHC protein expression and sarcomeric incorporation was observed as soon as 1 day after gene transfer. Effects of ß-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 {alpha}-MyHC with ß-MyHC attenuated contractility in a dose-dependent manner, whereas calcium transients were unaffected. For example, when ß-MyHC expression accounted for {approx}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 ß-MyHC, leading to 38% ß-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 ß-MyHC expression (18%) have Ca2+ transient-independent physiologically relevant effects to decrease intact cardiac myocyte function. We conclude that ß-MyHC is a negative inotrope among the cardiac myofilament proteins.


Key Words: adenovirus • contractility • gene transfer • intracellular calcium • muscle contraction • myosin • ventricular myocytes




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