Calcium-independent negative inotropy by β-myosin heavy chain gene transfer in cardiac myocytes

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

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)1182-1190
Number of pages9
JournalCirculation research
Volume100
Issue number8
DOIs
StatePublished - Apr 2007

Keywords

  • Adenovirus
  • Contractility
  • Gene transfer
  • Intracellular calcium
  • Muscle contraction
  • Myosin
  • Ventricular myocytes

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