Statins stimulate RGS-regulated ERK 1/2 activation in human calcified and stenotic aortic valves.
The signal transduction activating extracellular-regulated kinases (ERK) is triggered by G protein-coupled receptors (GPCR). In turn, the GPCR are mediated by G(q) and G(i/o) proteins subjected to regulation of regulators of G protein-mediated signaling (RGS) proteins. This network compiles extracellular growth signals to intracellular targets of sclerosis on calcified and stenotic human aortic valves (CSAV). Statins are known as partial inhibitors of atherosclerotic inflammation on CSAV. This study identifies descriptively the role of statins on RGS subjected ERK activation on CSAV. We collected human CSAV with (n=10, CSAV+) or without (n=10, CSAV-) at least 4 weeks of statin pre-treatment and investigated gene-profiling of RGS proteins, intermediaries and ERK using microarray technique, real-time and semi-quantitative PCR. Human non-calcified aortic valves were controls (n=6, C). Immunohistochemical stainings defined activation of expressed ERK 1/2 on CSAV (+/-) or C. As compared to C, in CSAV- several cardiac expressed RGS proteins were translationally upregulated: RGS1 (2.6 compared C), RGS3 (3.1), RGS5 (2.1) and RGS8 (2.5). In CSAV+, statins neutralized observed RGS expression. ERK expression was found unchanged in all valves: CSAV-, CSAV+ or C. In contrast, immunohistochemically we found enhanced activation of phosphorylated ERK in CSAV+ as compared to CSAV- or control. This study shows reduced RGS protein expression through statins leading to increased activation of ERK on human CSAV. In regard to known studies, the partial therapeutical failure of statins on severe end-stage CSAV is due to the induction of ERK activation which offers the need for more investigation.
Anger
Thomas
T
Department of Cardiology, Friedrich-Alexander University of Erlangen, Germany. th.anger@arcor.de
El-Chafchak
Jamal
J
Habib
Anissa
A
Stumpf
Christian
C
Weyand
Michael
M
Daniel
Werner G
WG
Hombach
Vinzenz
V
Hoeher
Martin
M
Garlichs
Christoph D
CD
D000328:Adult; D000368:Aged; D001021:Aortic Valve / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000378:metabolism / Q000473:pathology; D002114:Calcinosis; D016022:Case-Control Studies; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020710:RGS Proteins; D048049:Extracellular Signal-Regulated MAP Kinases