RhoA-ROCK signaling is involved in contraction-mediated inhibition of SERCA2a expression in cardiomyocytes.
In neonatal ventricular cardiomyocytes (NVCM), decreased contractile activity stimulates sarco-endoplasmic reticulum Ca(2+)-ATPase2a (SERCA2a), analogous to reduced myocardial load in vivo. This study investigated in contracting NVCM the role of load-dependent RhoA-ROCK signaling in SERCA2a regulation. Contractile arrest of NVCM resulted in low peri-nuclear localized RhoA levels relative to contracting NVCM. In arrested NVCM, ROCK activity was decreased (59%) and paralleled a loss in F-actin levels. Y-27632-induced ROCK inhibition in contracting NVCM increased SERCA2a messenger RNA expression by 150%. This stimulation was transcriptional, as evident from transfections with the SERCA2a promoter. A reciprocal effect of Y-27632 treatment on the promoter activity of atrial natriuretic factor was observed. SERCA2a transcription was not altered by co-transfection of the RhoA-ROCK-dependent serum response factor (SRF) alone or in combination with myocardin. Furthermore, GATA4, another ROCK-dependent transcription factor, induced rather than repressed SERCA2a transcription. This study shows that contractile activity suppresses SERCA2a gene expression via RhoA-ROCK-dependent transcription modulation. This modulation is likely to be accomplished by a transcription factor other than SRF, myocardin, or GATA4.
Vlasblom
Ronald
R
Laboratory for Physiology, Institute for Cardiovascular Research (ICaR-VU), VU University Medical Center, Van der Boechorststraat 7, 1081 BT, Amsterdam, The Netherlands.
Muller
Alice
A
Beckers
Cora M L
CM
van Nieuw Amerongen
Geerten P
GP
Zuidwijk
Marian J
MJ
van Hardeveld
Cornelis
C
Paulus
Walter J
WJ
Simonides
Warner S
WS
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D054460:rho-Associated Kinases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D020742:rhoA GTP-Binding Protein