title: Impact of acute and enduring volume overload on mechanotransduction and cytoskeletal integrity of canine left ventricular myocardium.
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 beta(1D)-integrin, melusin, Akt, GSK3beta, 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). 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-GSK3beta to GSK3beta (+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-GSK3beta, and MLP, indicating a strong drive to compensated hypertrophy.
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht, 6202 AZ Maastricht, The Netherlands.
authors.forename: Dirk W
authors.initials: DW
authors.lastname: Donker
authors.forename: Jos G
authors.initials: JG
authors.lastname: Maessen
authors.forename: Fons
authors.initials: F
authors.lastname: Verheyen
authors.forename: Frans C
authors.initials: FC
authors.lastname: Ramaekers
authors.forename: Roel L H M G
authors.initials: RL
authors.lastname: Spätjens
authors.forename: Helma
authors.initials: H
authors.lastname: Kuijpers
authors.forename: Christian
authors.initials: C
authors.lastname: Ramakers
authors.forename: Paul M H
authors.initials: PM
authors.lastname: Schiffers
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
authors.forename: Harry J G M
authors.initials: HJ
authors.lastname: Crijns
authors.forename: Paul G A
authors.initials: PG
authors.lastname: Volders
mesh_terms: D000208:Acute Disease; D000818:Animals; D002908:Chronic Disease; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism* / Q000473:pathology; D004285:Dogs; D005260:Female; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D040542:Mechanotransduction, Cellular; D011312:Pressure / Q000009:adverse effects*; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*
chemical_list: D003598:Cytoskeletal Proteins