Key result
Deletion of miR-22 in mice impaired inotropic and lusitropic responses to acute stress and sensitized them to cardiac decompensation and left ventricular dilation after pressure overload.
miR-22 plays a critical role in integrating calcium homeostasis and myofibrillar protein content during cardiac stress, protecting against heart failure.
miR-22 may protect against stress-induced HF; animal data leave clinical translation open.
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 Ca(2+) load in association with repressed sarcoplasmic reticulum Ca(2+) 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 Ca(2+) homeostasis and myofibrillar protein content during stress in the heart and shed light on the mechanisms that enhance propensity toward heart failure.
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Gurha et al. (2012) studied Cardiac decompensation and left ventricular dilation. Knockout of miR-22 vs. Wild-type mice was evaluated on Inotropic and lusitropic response to acute stress and cardiac decompensation after pressure overload. Deletion of miR-22 in mice impaired inotropic and lusitropic responses to acute stress and sensitized them to cardiac decompensation and left ventricular dilation after pressure overload.
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