Dataset Information

Targeted deletion of microRNA-22 promotes stress-induced cardiac dilation and contractile dysfunction.

ABSTRACT:

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.

SUBMITTER: Gurha P

PROVIDER: S-EPMC3503489 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Publications

Targeted deletion of microRNA-22 promotes stress-induced cardiac dilation and contractile dysfunction.

Gurha Priyatansh P Abreu-Goodger Cei C Wang Tiannan T Ramirez Maricela O MO Drumond Ana L AL van Dongen Stijn S Chen Yuqing Y Bartonicek Nenad N Enright Anton J AJ Lee Brendan B Kelm Robert J RJ Reddy Anilkumar K AK Taffet George E GE Bradley Allan A Wehrens Xander H XH Entman Mark L ML Rodriguez Antony A

Circulation 20120508 22

<h4>Background</h4>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.<h4>Methods and results</h4>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 vent ...[more]

PMID: 22570371

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Project description:Background: Guided by long-term safety data for AAV5 in humans, our translational study investigated whether AAV5 effectively delivers genes to healthy and achieve therapeutic efficacy in dysfunctional human-sized hearts, using a clinically applicable mode of administration and vector dosages. Methods & Results: In a first biodistribution study, AAV5 (11013 vector genomes; vgs) - carrying the reporter gene luciferase (luc) - achieved broad and homogenous transduction of the left ventricle (LV) of healthy German farm pigs 30 days after percutaneous catheter-based retrograde intravenous delivery (CRID), as measured by vector genome and luc mRNA assessments. Both its myocardial and extra-cardiac distribution patterns were advantageous compared to AAV9-luc and AAV6-luc. Using the cardioprotective human gene S100A1 (hS100A1) in a subsequent therapy study, effective myocardial transduction with AAV5-hS100A1 (11013 vgcs) by CRID prevented LV myocardial infarction (MI) enlargement and improved systolic contractile performance after 3 months in a porcine model with chronic post-MI cardiac dysfunction, as assessed by serial cardiac magnetic resonance imaging. The use of a cardiac-biased promoter ensured cardiac-targeted hS100A1 expression without signs of clinical toxicity, as shown by RT-PCR analysis, clinical chemistry and blood count. A previously unknown anti-inflammatory effect of hS100A1 in damaged myocardium, detected and linked to the therapeutic actions by a cardiac transcriptome weighted gene coexpression network analysis, was confirmed using AAV5-hS100A1 therapy in a post-MI mouse model, as measured by RT-PCR and echocardiography. Conclusion: Providing the clinically relevant proof-of-concept for AAV5 to effectively transduce healthy and dysfunctional human-sized hearts, its clinical long-term safety, scalable producibility as well as low pre-existing immunity in humans may predestine AAV5 as an effective and safe gene carrier for a prevalent disease as chronic heart failure, using therapeutic genetic effectors, such as hS100A1 or others.

Dataset Information

Targeted deletion of microRNA-22 promotes stress-induced cardiac dilation and contractile dysfunction.

Background

Methods and results

Conclusion

Publications

Targeted deletion of microRNA-22 promotes stress-induced cardiac dilation and contractile dysfunction.

Similar Datasets

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