Accelerated development of pressure overload-induced cardiac hypertrophy and dysfunction in an RyR2-R176Q knockin mouse model.
In response to chronic hypertension, the heart compensates by hypertrophic growth, which frequently progresses to heart failure. Although intracellular calcium (Ca(2+)) has a central role in hypertrophic signaling pathways, the Ca(2+) source for activating these pathways remains elusive. We hypothesized that pathological sarcoplasmic reticulum Ca(2+) leak through defective cardiac intracellular Ca(2+) release channels/ryanodine receptors (RyR2) accelerates heart failure development by stimulating Ca(2+)-dependent hypertrophic signaling. Mice heterozygous for the gain-of-function mutation R176Q/+ in RyR2 and wild-type mice were subjected to transverse aortic constriction. Cardiac function was significantly lower, and cardiac dimensions were larger at 8 weeks after transverse aortic constriction in R176Q/+ compared with wild-type mice. R176Q/+ mice displayed an enhanced hypertrophic response compared with wild-type mice as assessed by heart weight:body weight ratios and cardiomyocyte cross-sectional areas after transverse aortic constriction. Quantitative PCR revealed increased transcriptional activation of cardiac stress genes in R176Q/+ mice after transverse aortic constriction. Moreover, pressure overload resulted in an increased sarcoplasmic reticulum Ca(2+) leak, associated with higher expression levels of the exon 4 splice form of regulator of calcineurin 1, and a decrease in nuclear factor of activated T-cells phosphorylation in R176Q/+ mice compared with wild-type mice. Taken together, our results suggest that RyR2-dependent sarcoplasmic reticulum Ca(2+) leak activates the prohypertrophic calcineurin/nuclear factor of activated T-cells pathway under conditions of pressure overload.
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, 1 Baylor Plaza, BCM 335, Houston, TX 77030, USA.
Ralph J
RJ
van Oort
Jonathan L
JL
Respress
Na
N
Li
Corey
C
Reynolds
Angela C
AC
De Almeida
Darlene G
DG
Skapura
Leon J
LJ
De Windt
Xander H T
XH
Wehrens
D000818:Animals; D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D048429:Cell Size; D018450:Disease Progression; D004452:Echocardiography; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism*; D006973:Hypertension / Q000150:complications*; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013997:Time Factors
D050778:NFATC Transcription Factors; D019837:Ryanodine Receptor Calcium Release Channel; D019703:Calcineurin; D002118:Calcium