Impact of acute and enduring volume overload on mechanotransduction and cytoskeletal integrity of canine left ventricular myocardium

Dirk W. Donker, Jos G. Maessen, Fons Verheyen, Frans Ramaekers, Roel L. H. M. G. Spatjens, Relma Kuijpers, Christian Rarnakers, Paul M. H. Schiffers, Marc A. Vos, Harry J. G. M. Crijns, Paul G. A. Volders*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Web of Science)

Abstract

It is poorly understood how mechanical stimuli influence in vivo myocardial remodeling during chronic hemodynamic overload. Combined quantitation of ventricular mechanics and expression of key proteins involved in mechanotransduction can improve fundamental understanding. Adult anesthetized dogs (n = 20) were studied at sinus rhythm (SR) and 0, 3, 10, and 35 days of complete atrioventricular block (AVB). Serial left ventricular (LV) myofiber mechanics were measured. Repeated LV biopsies were analyzed for mRNA and/or protein expression of PID-integrin, melusin, Akt, GSK3 beta, muscle LIM protein (MLP), four-and-a-half LIM protein 2 (fh12), desmin, and calpain. Upon AVB, increased ejection strain (0.29 +/- 0.01 vs. 0.13 +/- 0.02, SR) and end-diastolic stress (4.8 +/- 1.1 vs. 2.7 +/- 0.4 kPa) dominated mechanical changes. Brain natriuretic peptide plasma levels were correspondingly high (33 +/- 4 vs. 19 +/- 1 pg/ml, SR). beta(1D)-Integrin protein expression increased chronically after AVB. Melusin was temporarily overexpressed (+33 +/- 9%, 3 days AVB vs. SR), followed by elevated ratios of phosphorylated (P)-Akt to Akt and P-GSK3 beta to GSK3 beta (+26 +/- 6% and +30 +/- 8% at 10 days AVB vs. SR). These changes corresponded to peak hypertrophic growth at 3 to 10 days. MLP increased gradually to maxima at chronic AN/B (+36 +/- 7%). In contrast, fhl2 (-22 +/- 3%, 3 days) and desmin (-30 +/- 9%, 10 days AVB) transiently declined but recovered at chronic AVB. Calpain protein expression remained unaltered. In conclusion, volume overload after AVB causes a transient compromise of cytoskeletal integrity based, at least partly, on transcriptional downregulation. Subsequent cytoskeletal reorganization coincides with the upregulation of melusin, P-Akt, P-GSK3 beta, and MLP, indicating a strong drive to compensated hypertrophy.
Original languageEnglish
Pages (from-to)H2324-H2332
JournalAmerican Journal of Physiology-heart and Circulatory Physiology
Volume292
Issue number5
DOIs
Publication statusPublished - May 2007

Keywords

  • hemodynamics
  • myofiber mechanics
  • serial intramural ventricular biopsies
  • cardiomyocyte remodeling
  • ventricular hypertrophy

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