Journal
CIRCULATION
Volume 125, Issue 22, Pages 2751-U209Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.111.044354
Keywords
cardiomyopathy, dilated; microRNAs; myocardial contraction; sarcomeres; heart failure
Funding
- American Heart Association (national) [10SDG2640137]
- Gillson-Longenbaugh Foundation award
- new investigator startup funds at Baylor
- US National Institutes of Health (NIH) [HL089598, HL091947]
- Muscular Dystrophy Association [69238]
- Fondation Leducq (Alliance for CaMKII Signaling in Heart)
- NIH [HL089792, K25 HL73041, R01 HL22512]
- Hankamer Foundation
- American Heart Association [09GRNT2170060]
- Ronalette and Berdon Lawrence Bone Disease Program
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Background-Delineating the role of microRNAs (miRNAs) in the posttranscriptional gene regulation offers new insights into how the heart adapts to pathological stress. We developed a knockout of miR-22 in mice and investigated its function in the heart. Methods and Results-Here, we show that miR-22-deficient mice are impaired in inotropic and lusitropic response to acute stress by dobutamine. Furthermore, the absence of miR-22 sensitized mice to cardiac decompensation and left ventricular dilation after long-term stimulation by pressure overload. Calcium transient analysis revealed reduced sarcoplasmic reticulum Ca2+ load in association with repressed sarcoplasmic reticulum Ca2+ ATPase activity in mutant myocytes. Genetic ablation of miR-22 also led to a decrease in cardiac expression levels for Serca2a and muscle-restricted genes encoding proteins in the vicinity of the cardiac Z disk/titin cytoskeleton. These phenotypes were attributed in part to inappropriate repression of serum response factor activity in stressed hearts. Global analysis revealed increased expression of the transcriptional/translational repressor purine-rich element binding protein B, a highly conserved miR-22 target implicated in the negative control of muscle expression. Conclusion-These data indicate that miR-22 functions as an integrator of Ca2+ homeostasis and myofibrillar protein content during stress in the heart and shed light on the mechanisms that enhance propensity toward heart failure. (Circulation. 2012; 125: 2751-2761.)
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