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

Departments of ¹Cardiology, ²Cardiothoracic Surgery, ³Molecular Cell Biology, and ⁴Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht and Maastricht University, Maastricht; ⁵Department of Anatomy and Embryology, Experimental and Molecular Cardiology Group, Academic Medical Centre, University of Amsterdam, Amsterdam; and ⁶Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands

Submitted 13 April 2006 ; accepted in final form 5 January 2007

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 _1D-integrin, melusin, Akt, GSK3, muscle LIM protein (MLP), four-and-a-half LIM protein 2 (fhl2), 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). _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 to GSK3 (+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 AVB (+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, and MLP, indicating a strong drive to compensated hypertrophy.

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

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